Dmd Seminar Shptsk

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GENETICS OF UCHENNEUSCULAR YSTROPHY

Ronald G. Wortonepartment of enetics and esearch nsute, The Hosptl for Sick Chden, andthe eatments of Meda enes and Bohyss Unvesity of Toonto Unversty venu Toonto ntao M5 Canada

Margaet W. Thompson

epartments of enetcs and ediarcs and esearch Insttute The Hosptal for ScChdren and he epartments of Medial enetics and ediatcs Universty of

Toront Unversty Avenue Toonto Onaro M Canada

I N T R O D U C T I O N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

CLACAL GENETIC O DUCEE AND BECER UCULARD T R O P . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

OLEULR GEETIC O DD D D 6

Man h DMD n Ch Ban 1 Conng of DN Sgnt fo t DMD Lou 66oaton of x qunc fo t DMD n 69a of t DMD n 6 1

UTATO AALY AD CLCAL ALCATO 6 Natu of Mutaton n t DMD n 6 1 Ca ntcaton an Pnaa Dagno 6 1

DYTROPIN TE PROEI PRODUCT O TE DMD GENE 6 1 6on of t DMD n 6 1 Dtn tuctu Duc fo cDN qunc 6 1 ocazaton of Dton n t Muc 61 Paton f th Da " 6 1 na Mo 6

APPICATION O REVERE GENETIC TO OTER DIEAE................ 6Contuou n yn 61/utoo anocaton 6

ONCLUION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1

0047/88/00 $000

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602 W & HM

INTRODUCTION

D s s (DD s X sas a

f a yas was f s xg a fsa ss cca gcs av f ca gc aacs, af a f a sv A as a a s ss c s s sss f asa av ss As as a s f w fs f ss a f f s sa afsas f sas8 102 109 11 12 T s ff s s f s a y a agss Dc fa

s Pscs f sag sas ag aaay a 983

w g ss f DD ws a a scfc g f Xs, sgs w v vs s fwg f s a s, yass w ag a d I s v s s ss s f g as sa f c xss (cDA a fa f s, g c f a a64. A sa f s a fa awa

CLASSICAL GENETCS OF DUCHENNE AND BECKERMUSCUAR DYSTROPHY

d ss D d B ss (BD v w wd 8, 9, 5) asa

Pas w DD s w sc wass a ag f2 ass a w a f s s svv

ws A ss fg s gss va v fs s (CK), sa sags f sas K s as va g a ss s f a w s f as, vg a sf g fvcarr s 8 9

BD ss D, d s sa s f s s, s, g svvay s w BD a f s s w s a a f 16 as a y ass sas s a

sv w DD a BD BD as ss asa cssv-g sca s a a cfs w f s f s (8 53 BD DD w w s s s , dsad DD

Bs DD s -d sj d v,

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DUCHENNE MUSCULAR DYSTROPHY GENETICS 60

xpssion in a popotion of carirs is to be xpctd. Accoding o onstimat (8) about 8% o aris hav som clinial manistaion ofmyopathy Th disod is also gulaly pd in mal cais with a

X kayoyp in som or all clls viwd in 7) As discussd blow, anumb of manising mals with X/autosom tanslocations hav bn ospcial signian fo ou undstanding o th disas.

Th pssion o DMD/BMD in monozygoic mal win cais hasbn of spcial intrs sic Gom ad ollagus potd sv clinialmanisations in on cai bu no in hr monozygoi win sist (47)Sval imila ca hav inc b pod viwd n 07 UnvX-inavation an bing about makd dsrpany in clnical xpssion ofan Xlinkd ait bwn mmbs of an idntical wn pair and studis o

on pai o DMD cais hav suggsd tha h win sists had pntially inaiat in X homosoms 5 Th possib mbyonilationship bwn th winning vnt and th dvlopmn o dintXinactivation pans n h cotwins rmains unla

os stimats o th incid o ar in th rang of7 to 9 x0- I in 00 in 700) mal bith, with litl if any hnic variation (740 0 7) Th muation a o clos o I x 0- is an od ofmagnitud high than most oh knon mutaion ats. Th tmly lagsiz of th ag o mutaional vnts (000 kb) plus muational hotspots inth gn appa o accoun fo his high a s blow)

Th qustion o a possibl s din in muaion at is o mo thanhorial impoanc sinc gntic counsling o DMD assums ualmuaton ats in mal and mal n accodanc wih h Haldan ul, hsassumption allows th alculation that on thid of all cass should sult fomnw mutation in th matnal gamt on thd by inhitan of th DDgn fom a arrir moth who is hslf a nw mutant and on thid byinhianc o a DD gn psn i an alir gnaion. Th suls o

sggation analysis in sval lag studis ( 74 0 Ill , 7 4) ain mos but no all cass consistn ith his pcation.Th lativ popotion o mutation at th lous that sult in BM ah

than M is small. Calculation by Haldan's omula with inss stimatdas 070 37 vals that only 0 of k patns a nw mutants Bis pord to account fo7% of mutations at th locus (0) with anincidnc of 55 x 0- Th cosponding mutation at would b455 x - about 5% of tha or D

MLECR ENETCS DMD ND MDng h n h n X1

Th is inication ha th gn sponsibl o DMD and BMD is in banXp2 in h Xchomosom shor arm cam fom a fmals wih th

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6 WORTO & THOMO

Duchnn o Bck phnotyp. n th lat 970 and aly 980 alad g dbd (16, 36 73 91 , 137) ah o ho had ad noo X autoo tanlocaton h a bakpont n band Xp gu

Th contnt nolnt o band Xp uggtd that a gn at tht ght ha bn duptd by th tanlocaton hl pntal nactaton o th unaangd X chooo a pud to lnc thcopondng nomal alll ladng to th phnotypc xpon o anX-lnkd da n a "ca al. al uth a (Fgu habn actand, and th xchang pont ha alay nold band Xp(d n 8, 0, 8 n th ca LP ak (77 o cytontc poyoph 46 08a ha dontatd patal ogn o thtanlocaton

Hgh oluton bandng analy o al o th tanlocaton aldhtognty o tanlocaton xhang pont thn Xp th o xchang n Xp . ot n Xp , and a at th cntoc d op. (gu (8 9 0. Snc band p. pan llon bp o

A.

p21

p2.

p2.

t(X;3)

B. eM C r Rca ]- 82. 10

C7} ] J 754-OTC 0L LkgMap

Figure Schematic o the three line o evdence mappng the DMD gene to ban Xp2.

A Csa azan ansan exange ons n eaes w OO BOHgh eoutn anng y oy uke (8) eeae a hetegenety o ehage onetween the uppe ege an Xp21 an the owe ege o a Xp23 a egon pannng aew mn bae pa DNA The a oatn hwn wee gnaly ee n eeene

4 6,36 70a 73 9 04 07a 22 an 37 Atna anatn not nue nthe oy an ue tuy ae fun n eeene 04a 0a an a

Seveal anonymo probe an the OT (othne tancabamylae gene map to the hotarm o the X chromoome,a hown. hee pobe revea RFP that egegate wth the DMDan MD phenotype n amile. The etmate genetc tance betweenM an the marke hown on he gh han cae n cM moe eae evew o he egegaon aa on n

Gooellow et a (4 an Woton rghe (32 The eletn n patent mcocopcay vbe an cone a comple phenotype thatnclue DMD XK GD R an mental etaaton (4 See tet or moe etal an oeeence to othe eeon patent D th ggete that heM gene mght e vey geo that ome o

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UC MUCUA TO TC 605

th xchang pont mght l outd th gn and dpt t actty thoughan ataton o chomatn conguaton that xtndd along th chomoom.Th molcla mappng o th xchang pont lat to thDMD gn

dcd n a lat cton.Th cond ln o dnc placng th DD gn at Xp cam omamly tud th D pob that dtct tcton agmnt lngthpolymophm RFL on th human X chomoom. Th t to lnkdmak o th DD gn th RL dtctd by th pob RC8 04and L l .8 Th RC8 clon mappd to th dtal thd o th hot oth X chomoom hl L 8 mappd to th poxmal thd Fgu B nDuchnn faml both polymophc mak ound to ggat thth DMD gn, but ach dplayd a combnaton qncy o about 0%,

placng th to pob at a lnkag dtanc o 0 cM om th DMD gnTh to pob mappd about 40 cM apat, ndcatng that thy mut flank thDMD gn mappng th gn to th mddl o th hot

Snc th ntal pot many mo Xp pob ha bn olatdmappd, and ound to b lnkd to th DMD gn at dtanc om 0 to 0cM 0 48. g B ho om o th pob and th tmatdlnkag dtanc om th DMD gn not a th to clot andompob 7 on th tlomc d 4 and 754 on th cntomc d o thgn 70.

n Bck aml, th am pob ald a ggaton patt mlato that o DMD, thby mappng t ponbl gn to band Xp andpodng th t ndcaton tat th uchnn om and th mldBck o mgt b cad by muaton n th am gn 80.

h thid ln o dnc placng th DMD gn at Xp2 cam om amall t o patnt th complx phnotyp includng DMD th on omo o al Xlnkd phnotyp ncludng glycol kna GK dcncy adnal hypoplaa H tnt pgmntoa R McLod ph

notyp XK and chonc ganlomato da CD yndom oDchnn dytophy coupld th HC, K dicncy and mntal tadaton MR had bn cognd n aml th to o mo actd mal,uggtng Xlnkd nhtanc and th poblty that th phnotyp ultom th dlton o th o mo contguou gn d n 4

lthough patnt ith DMD and GD o XK th GD had bn knono om tm th t conct dnc o a dlton o contgo gncam om tdy o BB, a patnt th DMD, CGD, XK, and R (Cytogntc analy th hgh olton chomoom bandng ald a

mall bt dtctabl dlton o pat o band Xp1 and p gu Vicaton that th dltd gnt a not ntd lh n thgnom qud tudy o th ctly t th tm, th andom DNgmnt, 754, gu B had bn hon to ggat at hgh quncyth th DMD gn 70. South blot analy o BB DN ald no

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606 WOTO & TOMO

hbidiation signal with pobe 54 damatic poo that thee was a deletiono DN om p2 wthout einseton elsewhee in the genome Subsequentl ote patients, each with multiple -linked disodes wee eex

amined b high esolution banding and tested o hbidiation to 4 andothe p pobes This evealed a numbe o deletons and conimed theconcept o complex phenotpes esulting om deetions o contiguous genesSeveal ecent papes evew the extent o the vaous eletons an clealyemonstate a most pobable gene ode o AHC GK DMD K CGD n a telomeetocentomee diection (3 9 30a 3 43 0) t isnotewoh hat two patients with isolated DMD have been descbed withctogeneticall vsble eletions extendng om 5 nto the DD gene (522

hus the combnaton o tanslocaton exchange points, lnkage analsisand contiguous gene deletions conimed the mapping o DMD plus sevealothe disease loci to p and set the stage o the gene cloning stategiesdescibed below

Cning egment rm the LThe human chomosome contains about % o the genome o 0000 kband the closest andom isolated segments wee about 0 cM om the DMDgene a phsical distance estimated to be about 0000 kb The olowingstategies wee designed to enhance the chance o ndng DN sequencesom wthn the DMD gene

ne stateg was a cleve but unotunatel unsuccessul attempt to clonethe gene b sceening an chomosomespeciic genomic iba againstcDN libaies pepaed om nomal muscle mRN in a seach o chomosome sequences expessed in musce The one candidate gene olatedwas an lne pseogene o the gydyd dydg gene whch tsel maps to chomosome 2 4.

Two othe stategies which wee designed to take advantage o uniquepatients with stuctual eaangements at the site o the gene have beensuccessul in isolating genomic clones om within the gene

The appoach o Kunkel and his coleagues 8 depended on the isolationo multple clones om wthn a small egon o the chomosome nown tobe elete n BB one o the patents wth a complex phenotpe (gue )The stateg is outline in igue 2 DN om an Y male (to enicho chomosome sequences was ceave wth the estiction endonuclease! Sheaed DN om patient BB was added in lage excess n a compet

tive hbidiation eaction the phenol enhanced eassociation techniquep to compete selectvel wth all sequences except those om theelete segent ollowng enatuaton an eassocaton hb molculscontaining two sheae stans o those containng a sheae san an andigested stand woul be eacto to cloning he ae bid mole

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MAR RO 607

cul coniting o two Iigt agmnt w compatibl with cloning into a Bam- clav vcto a th molcul w nich oqunc om th gion lt in BB inc t wa no compting

a D om thi gion (86 Following pRT aociation t natu D wa lgat to a amclav plami an th ulting libay wa tt clon by clon to intiytho clon tat mapp within th BB ltion. mong a w hunpRT clon analy igt ail to ybii to a out blot o Dom BB an to mapp witin t BB ltion (86, 98

ac o t clon wa tn tt o ybiation to D om a io mal DMD patint on th aumption that om patint might havltion o all o a potion o th gn an that any pRT clon tat

ail to ybii wit t patint D migt map witin o clo to tn mon t it pRT clon om witin t BB ltion, on clon

A T

XXXXY

M=M

MM

BB

B X ; 2 ) 2 ; q2)

" N

X 2 () (2)

Fg Shea o ilsrae he o sess onng sraegies.

The pERT conng scheme s descbed in he e . The ends of the dgested moleclesare ndiated as (dobe sranded or m (snle sranded The ends of the sheared moleclesare nabeled mong he rassoaed moeles on he peecl algned dgestedmoleles are onabe, and hese are enrhed for seqenes mssng fro the NA of paen

. The ransoaon jnion lonng sheme s desrbed n the ex The der( and der1

hrmosoes rm he ( ransloaon paen A, ere separaed fro oher ribosomagenebearng hrmosomes b segregaon in oati ell hbrds an rbosoa gene probes sed to denif and lne a NA rage panning he jntion J The hromosomesde of the ntion as eped o be dervd fom he gene. he blok of rbosoagenes dsrped b he ransloaton s mared rNA Onl he shot ars of he hrmosomesare shon

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608 WORO & HOMO

pR87 seee t be te sest sie DN 7 DD patietsake te pR87 seqee (98)

he pR87 sequee e beame he sapit a biietia

hmsme ak a a ma msme by he sequeia isaiveappi phae es a hse eihe ibay 86 99100 vetay 220 kb e X se was isate a tis DNseet was ive e s esiati DXS164. Di he hsmea sevea sie py semes ee ieiie a he is hee hesep8- 88 a 8- ee isibue may abaies au hew aaysis paie DN weyive abaies ibute ata eeis a a ta 88 eeis wee ee i 146 patietsexaie (8 ve a tese the eeti extee t e etieDXS164 ei but i se paies the eei exee itiDX164 twa eithe te eee te eee ie these eetisi t eie a ii ei veap it appeae that thee st beeeets the DMD ee bt sies te DX164 s Hweve epatiet ha a 4 kb eeti witi te DX164 s suesi tat aimp pa he ee mu eie ihi hi ei T he eeiases 85 a hes epe subsequey 5, 7 ee assiie as MDii hat MD a DMD ae ause by aei atis (8

eaie map e epis may ese eeis is pvie byMa a eaues 96 he psii a ietati e pRT8pbes i he DX164 us is sh i iue

ie he DX164 us seeme by eei aaysis be pa heDDee it as atiipate tha p pbes sh ivaiaby seeate withte DD ee i aiies me he pR8 pbes wee u t etetRFLs a whe ese ee se as akes i aiy sies tey seeate wit te uat ee i y 95% eises (4a 40 e 5%ebiai ae as pui a iiae a aveae eei istae

5 M bewee pR8 pbes a he tai sie a est whi as siebee estate t be ue t itaei ebiati a t isassiiai aies wi aa saiis (see bew

e eu ate t a isssi he DXS164 us i eti wiisati epesse sequees

he se suessu appah eai heDD ee as a ake byu p Te appa was epee the ieiiai a tasati eae wit a eaaeet that pae te asate seet e se aaet t a bk taemy epeate ees ei

the 8 a 8 ibsma N ( (iue . ibsma DN(DN pbes isae i he abay . hmike ee use ieiy a e he paie a seme DN ha spae heasai ui (8 his e seme as btaie m amseua smai e hybi aii he e( (Fiue

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H MAR TROH T 09

ralocaio cromoome (1). Te ybrid cell lie ad bee clred formay mo o llow me or e lo o m crocerc cromoomewic ogee cry coie o e ibooml gee ereby imli

fyig e erc for a XrDNA jcio fragmeTe jctio cloe deigted XJ coied 20 bp of rDNA at oe edd abo 1 1 kb of X-cromoome eqece at te oer. romoomewlkig from X alog a ormal X cromoome yielded bo 120 kb of ema X cromoome (te DXS20 oc) derived from bo ide of ejctio ite Wit te DXS20cus tree bcoe X . 2 ad 2 detected F tt egregted i Dce familie wit te DMD mttio. ike T87 X robe owed approximaely % recombitiobewee e robe ie d e DMD mio ( 1 1) d deeced deleio i

abo % o male aie (18)Figre ow te relaio betweeDXS20adDXS14 o te ort armof te X cromoome. ice te XJl cloe cme from te der(X) cromoome (Figre 2) cyig X comooe eqece from e cetroericide of e jctio i provided a oriettio of te DS0 loc wireec o e ceromere ad elomere. Te T87 robe were fod toybridie wit DNA fom te omtic cell ybrid lie caig te der(21)raloctio comoome (igre 2) b ot e dr(X) cromoome tereby mapig DXS14 o e teomeric ide ofDXS20(85) Paie wo addeleio of DXS20 ad e T 871 ed of DS14 rovided eorieio o DXS14 o e romoome () velly comoomewakig cloed te gp betwee DXS4 ad DXS20, wit 17 kb beweee origil pRT87- cloe d te Xl cloe t te t(X21 ctio. ecombied wlk covered 40 kb of e X cromoome.

efore e iolatio of cDNA cloe tere wa coiderable certaiy ao weer te DXS14IDXS20 regio wa iteal to e DMD gee. We ipaticlar were coceed t e t(X;2 1 ) ralocio mig ave ivolved

a bmicocoic deleio of everal dred kb a removed eDMD

geeI i wa e cae e XJ1 cloe cod ve bee derived from a eqece coiderble ditce from te DMD gee o orml cromoome Tipoibiiy wa elimiated by te ioio ad eqece alyi o tet(X2) tralocatio jctio from bot derivaive cromoome eqecig revealed mall deletio of abo 2 bp from e rDNA comple ocromoome 2 ad bot 70 bp fom te X comoome () Te lck of amjor deltio reiforced te cocep tt te ralocatio ad caed tedieae by dirpio of gee e ite of e ralocaio Addiiol

eidece cme om e idig o ie wi deleio coied o eDXS20 lo 1 18Isotion of Expresse Sequences from the DMD Geneice te eidece wa trog at te DXS14 adDXS20ci were wiior very coe o teDMD gee te raegy o locae exo of e gee wa o

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6 0 WOTO & THOMSO

p21.3

p21.

OXS164

OXS20

DMD geicee cles of cgsequece

I

_41 .,_ 3 '

[ GMGXI1

P0S

J-r

astes

r X3)';S(4)J dee

HTSPT

eio

754 +54

I"' t(X;)

K6 GOo RP9 0T

HIP5exon /

'(XHHIeo

j.x 2 : tX5)

exn U '(X1)ER rme4

Sf 1mp k-bses00

000

500

Figur Genoc o the DMD gene. he ecton on the left how the elton betweenbd 1 nd the ognl ER8 nd egon (DXSl ndDXS206). Thee wthnheDMD gene nd e flnked b he GKndAHC gene on he eoec de nd heXK CGD

P d TC gene on he centoec de he nonou obe nd 4 e decbed ngue Pobe Kunke t a, 86a) nonolohc nd t e kb foDMD Pobe .4 ( oxl oDMD obbl between he TC nd 4 loc. nth tc dg on he DXS nd DXS06 oc e dwn o the cle on the ghhdde. heDMD gene hown n the dde of the gue nd dwn o the gh de. Bede thegene chetc of he vou cloned egon dcued n he e. he "ju clone JB JMD nd 4 wee deved b olton of deleton juncon cone wth RT8 obend e theefoe hown ched to he DXSl locu b dhed lne ER84 w ndeenden cone deved o the ogn ER ceen nd w lte hown o ne heft exon of the gene he cone GMGl l P IP nd the elg wk edcued n the ext The DS06 locu w exded o t n kb e b codwlng wth cN cone obe w eended though eon n contnuou bockEon nd 2 e on cod ht hve not et been nked o ech ohe o to the DXS06cu t e ttc t t DS cu T cm c cteon 1 o ce the ooe of he gene (8) nd he G nlocton t gn (82) .Mn o thee genoc cone hve een ed b GE o GE n ono ecc S

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DUCHENNE MUSCULAR DYSTROPHY GENETICS 61

test idividual geomi subloes for hybridiatio with expressed sequeesNA or cDNA) from muscle ad/or o test for sequeces coseved arossspecies Moao et al 1) reported the first exos i the l6 locus by

idetifyig a subcloe pET725 that hybridied with mokey boviemouse hamster ad hike DNA i a oo blot. The pET725 loeotaied a exolike sequee ope readig frame with appropriate 5 ad3 splie jutios) that was oserved preisely i mouse DNA revealed amessage of -16 kb later estimated at 1 kb) o Northe blot aalysis ofmuse ad detfied a lkb DNA loe from a fetal skeletl musle DNAlibary. The cDNA cloe cotaied 8 exos that mapped ito the 164lous over a spa of 1 kb igure ) equee aalysis idicated a oretatiowith ascriptio i a ceomeretotelomer diectio. escreeig of he

DNA librry allowed isolatio of overlappig DNA loes orresdigevetually to a omplete represetatio of e 4 kb asrpt 2) The ompleteset of DNA loes hybridie wit at least 6 differet d l fragmets ogeomic oute blots ad sice e cDNA otas few d l sites mostfragmets must otai oe o more exos of the gee The st exocotaiig agmets mapped over a geomic distace of b suggestigtat the total gee might be about 2kb i sie.

I our ow laboratory a extesive search for coseved sequees withithe 206 lous iitially failed to yield positive results a cosequece ofthe fat that the 206 lous 1 kb at the time) otais a itro of 1 1kb suroudig the tX;21) trasloatio jutio Evetually two subloesfrom XJO XJ l O 2 , XJO3 loated about kb o the telomeri side of thetX2l) jutio Figure 3) idetified a 2kb DNA from a adult musleDNA library 1) This DNA loe cotaied the first 1 exos at the 5ed of the gee with exos 17 mappig o the der) chomosome adexos 1 o the e) chomosome 1) thus cofrmig that the t)tasloatio had disupted the gee to ause the disease Several of the exos

o the 3 side mapped to the164

lous ad were idetial with the firstset of exos idetified by oao ad olleagues l) A liear map of all

fgmt ThSI m ( 1 2 ) how o th ight wh fgmt z kb) Th oi ccl i h w cu with h zm whl th o cc t i ht il oct om molcu h o mhltio 1 1 . Th muo t how icvl tloo chg oit ht hv m ltiv to gomc ob b Bo ( g o BB o ( o oo h h x igmm o h cN m o igu Exo 1 2 li i hD64 locu xo 8 th oigil D06 loc Exo 3-7 lik i thD06 loc x b comiwkg Th itc bw xo 2 btw 3 4 kow bt how tob lg bc xo 1 l ERT84 v mm c ERT8 th comic of h 2 kbSIgm ( 12 Th ov 4 xo bov thD64 loc (8 hv o b ccu m th 3' of h g i i Thmmum iz of th g o b bou 2000 b.

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6 2 WRN & HMPSN

e eocoaiig dIII fagmes is ovided by Koeig ad coleagues2) A mo deaild ma of e fis 20 exos is aig comleio as ecDNA obs a be sed o xed e DXS206 ocs by e isoaio ofcosmid cos coaiig muc of e 5 ed of e gee 95) icludig omoe egio )

Cartogaphy of the DMD Gene

Wi a gee of is si igu ) coveioa sticio maig isiadua b ew cis of lsd field g eecooesisFE) d fid ivesio gl lcoosis FIE) ae bee idal focosucig ogage esicio mas of lage DNA fagmes 20 12). o simliciy oly e I sis e sow i ige . T

esicio ma is acoed o e DMD ma by eSfH sie i DXSl 159 21). evea oe geomic cos ae deiced i igu ad sese as usfu ladmaks o gomic ma. T "jum clos JJMD J-i ad J-66 wee all obaied sig ET7 obes o deec adisolae abea esicio fagmes a saed e deio jucios offou aies wos deios dd fom 14 o egio of "jum coe 9699) ac "jum co squec fod e basis fo socomosomal waks o isoae e geomic gios idicaed Te cloHI25 ige ) was isolaed by Davies' go wi a eciqe aalogos oET, bu usig ig iogaic osae HIP) o ace eassociaio). T cloe HH was obaid b a comosoma o HIP HP) fomHIP 9). A oio of S164IXS206 oci as aso bee isoaed byHeilig e a 9) by a scod isoaio of e X21) jucio followed bycosmid walkig Heilig walkigu ) Te ob P0 was isolaed byWaeaa e a 12) fom a cosmid libay of a ams-ma ybid celcayig a a of e Xcomosome so ad maed io e DMDgee. T coe MX was isolad by illd 6) fom a ow-soed Xibay ad maed io e

MDgee

T iiial DXS206cus of 20 kb lef side of Figue ) was dd oiclde eos 7 midd of ige ) by sig cDNA obes o ideifyeo-coaiig cos mid coes oeig 20 kb. To dae e ma beweeos 1 ad emais icomee

UTATION ANAYI AN CINICA AICATION

ocaiaio ad coig of e gee immediaey alows fo e sudy of eae of muaios i gee ad e alicaio of is kowdge ocaie ideificaio ad eaal diagosis

Nature of Mutations in the DMD GeneWiou doub e majo fom of muaio i e ge is deeo. No oyae lage deeios comassig wo o moe gees bee isumea i

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CH MSCAR SROH S 6

maig seral gees to bad X but itragei deletio is te mostommo cause of DMD/MD ( ) Te deletios do ot ouruiformly oer t g I te DXS164IDXS206 rgio te frqucy isbeow 0% (57 5 1 ) wereas dltios ear t middle of t gedetectd wit cDNA robs (1 ) or wit rob 0 () occur wit aigr frquy A total of 10 atits i Kukels laboratory () ad aadditioal 10 atits i our ow laboratory wr studid wit DNA robsorig t tir g ur ow data ar rstd i igur ad clarlyreal t oradomess of t deltos o t DNA ma. T clustrddeltios tat begi o of re iros ear 67 b o DNA ma aeo bee arateried i detail A realisti ieretatio is tat e itroscotai sques tat redisose to rearragemet () Te altatie

xlaatio tat t iros ar extraodiarily large aars uteabl sicee dletio breakoits ar clustrd ito a 50 kb itral of t geomima (1)

Dletios aar to occur wit aroximaly equal fequcy i DMD adt milder MD (1 57) ques dltd i DMD atits may also bedeltd i MD atits ad dltio ie dos ot orrlate wit t seerityof te disase ( 57 90 9) A attracti yotesis is tat DMD resultslargly fom framsift deletios wil MO usually esults fom dliosta maiai te raslatioal readig fram as bee ossible to s e

yotsis sice t itroexo boudaries are kow for t first 0 exos(95 9) so tat deltios cofid to tis rgio may be classified asframsift or oframsift Aalysi of OMO ad MO atits byMoao t al suortd te yotsi (97) I cotrast our ow daa o 9atiets do ot suo suc a simle modl (95) si sral mild MOatiets ad fram si deltios of exos 7 Te ossibility tat futioalrotei migt be rodcd by riitiatio from a iitiatio codo i xo was suggested (95)

Aoter ty of mutatio mu lss commo ta deletio is itrageidulicaio (7). Tos aalyed to da i our laborato (Figure 4) aearo duliae oe or a few exos by adem duliaio of a oio of ege rsumably by uqual rossg oer betwe riie elemes(7)

Deletios ad dulicatios ae ot bee rcogid i affectd fmalsexet i oe femal wit a 5X cromosome ostitutio wo ad adeltio witi e lous (0) resumably su muatios i etoygoteswould ot b exrssd T mutatios at are exrssed i femals are te

traslocatios disussed earlir ad may of tese ae ow bee sow tobrak witi t DMD ge (Figur ) (reiewed i 10)To dat o oit mutatios or slice utio mutatios a bee idti

fied but tis migt simly relat to t orwlmig task of fidig ucmutatios i a 2000kb ge

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64 WT THM

XJ PERla7

-

13973 bp5' 3

368

Cln-bg p hc semt cyO-h roCoaln : '250m domin dmon

hi o h h poi po ophi h 1 97 bp NA i hown wih it 69 o mo xon h fit 1 xon hv bnhid i dti nd h xon dwn o ( 9 h ining xon ppoxiion dwn fom Konig t ) . Abov h xon p th hv b dint th

xtnt of ight piion dttd ong 0 M pain xind in o boor 7) h thin b dint th xtnt of 6 dtion ong th ptint h pt ofdtion with dtion tpi fond in th fit thid of th gn nd g nb ofdtion td in th idd of h gn i mb ii to th ptt fond bKonig t () o n indpndnt t of ptint ow th xon p i hti o thpi t of h 65 ino id potin tn fo Konig t () h d bon h mino tmin i h gion of ph tinin hooog with potnti tinbindingdomin h nx domin ontin h 6 pini pt o o thm nbd hgin of h fit ix p oinid wih xon bondi with on wo o th xonnoding on p nit ( h thid domin i th high tin gion wih h potnti

+ binding it E hnd) () Th domin h no ditingihing nd nohomoogy o kown ptcin (.I

h pditd ti tt o th poin (phoogph podd fro C withpmiion) ( h imiit o o protin i did in h t

Carrier dentiatin and Prenata ianiMolclar aalysis is ow idissabl or carrirocarrir idtiicatioad ratal diagosis i DMD ad MD T rimary moclar diagosticmtod as b by liag aalysis wit gomic robs tat rcogi

olymorisms witi ad aig t g T may sc ros tat avb idtiid om o wi r ow i igr allow tracig o tDMD rgio o t cromosom trog most amilis ad idtiicatio omay dltios ad rcombiatios ctly cDNA robs wic allowdirct dtctio o vitally all dltios av bcom availabl

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H MA OH T 6 5

Itrageic deetio are revealed by failr of probe to hybridie withgeomic DNA o far, with a igle poble exceptio (8), male fod tohave itrageic deletio have bee affected With cret techology it i

poible bt difficlt to ditigih i female betwee homoygoity adhemiygoity for a maker o the bai of the iteity of the hybridiatiogal, bt preee of a gle marker at a ite where heteroygoty expected ambigoly reveal a deletio.

I everal large tdie it ha bee how that the great majority of wome,eve thoe who have oly oe afected relative ad ormal CK activity caow be claified a caier or ocaier with greatly impoved accracyover that attaied by pedigree aalyi ad CK aay aloe Ue of itrageicprobe a well a akig probe add coiderably to the likelihood of

fidig iformative marker ad th of chagig a ambigo etimate ofcaer rik to the pper or lower limt of the rk rage la , 9 , , .

Whe a family ha oly a igle affected male (by far the mot commoitatio , it may be impoible to detemie whether the mother i a caier orthe patiet a ew mtat, bt preatal exclio may till be poible o thebai of which materal chomoome ha bee tramitted to the fetimilarly a iter of a deceaed male may be oered preatal exclio if herparet marker are kow ice the rik to her fet travel with her

materal marker.Whe a woma i a carrier ad ha formative fakig marker of kow

ikage phae preatal diagoi i poible with p to % accracy a loga there ha bee o reombatio i he rego laked by the probe drgmateral meioi ecombiatio, whch occr i a igificat propotio ofcae, prevet accrate predictio of the fetal geotype becae of therelatively low level of reoltio of alyi by liked marker ad the kowheterogeeity of mtatio ite withi the loc Dara ad colleage (8)have emphaied the avoidable certaitie i the e of likage, decribig a cae i which doble recombiatio which i detectable led to thebith of a affected child who had be jdged to have a low rik ch afotate coclio reflect a limitatio iheret i the techiqe.

Difficltie may alo be ecotered whe DNA from family memberimportat to the aaysis caot be obtaied o example a patiet may bedeceaed by the time hi iter preet for preatal diagoi , father importat to the aalyi may ot be available, or paterity of female familymember may ot be a repotd Additioal poblem iclde the legth ad

eee of the ocede eecially if the earh for iformative markeri ot iitially ccefl.he recet iolatio of cDNA cloe offer the poiblity of direct preatal

diagoi i the large poportio of famiie i which a deletio mtatio ipreet withot the eed for exteive family tdie or the rik of detected

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6 1 6 W HMS

recombato 29. Ths appoac s kely to be wey use for preataagnsis n fas wt tn tatns cas t s nt ny gyr, t tntay fastr and r cnc tn nag nyssDtn tstng wt cDNA rs rqurs Suth t aayss wt ammum of sx cDA pobes, eac etectng 10 r ore bans a botTe use of a pomerase ca reacto (PR) to ampfy specfc exos thatay the be tcte y ge ectropress wtot th nee for ttngwtt and wtt autragray ds grat rs fr a ctgn nayss n ss thn n dy f rcpt f t s (J. S Cra, prso comucato. The t requre for te aayss s potatsce preata agnoss for DMD s preferay prore y coroc vussampg, wth a vw to trnatn f prgancy n t frst trmster f th

ftus s an affctd a.Grna sacs, rary dscrd fr tr an dsrdrs, ay nt

uncn n DMD/BMD. In svr rrtd pgrs a rnt wthut eeto somatc ce DNA as eveteess transmtte a X cosoewt a dtn t r tan n ffsprng (2 26 7 0) T mst kypossbty s tat t transttng parnt s a sac wt dffrnt c nspreset soatc an gera tssu a msacs of te gea tssuetsf has n rprtd (26 10). Tg grna scs as tantgeetc pcatons, ts ncdnce and trfr ts sgnfcance fr genetc

cnsng s st unnwn At ts t f a affctd y as a dtn tats nt rsnt n s tr's satc cs, t tr and r rst-dgrfa ratvs cannt assd t nncarrs; and ty sod st oerd carrr testng and prnata dagnss (26)

Ufotuatey car etecto preata agoss, ev y the ostectv tcnqs, tt t rdc t vra cdnc f DMD sncst ptnts ar t y ffct rs f tr fs. A stp tat cnp t ruc t ncdnc s nnt scrnng, wc ffrs a as fprvto t t of scon acd oys n ndrds At prsnt aout

10% of DMD patts r secon css tr fmes, bo bfor thsease s xpresse a or cose reatve Neonata screg fr DMDan BMD s fas a s us se eas (5 12) Popat scegfr trzygts, wc c as ad n rvntn, s nt ss at prsnt.Nnat scrnng fr DMD s crtczd y s n ca grnds cas ntratnt s avaa. If aratn f ts tragc dsas cs ss,eoata screeg w be uc or wey accepte

DYSON, ON ODUC OF DMDENE

T gtm g f t cua gtc ppc s n t us t gnas a steppg stoe to te pote a tus to an unerstg te sease

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DUCHENNE MSCLAR DYSTROPHY GENTICS 61

Te recgit tat te DMD gee ecde a arge rtei triggered eayecati tat ebi a arge MW rtei f te mce rcmere migtbe te gee rdct 29 Hwever te fdig f a ma amt f

ebi i dytric mce tie ( 17) ad te recet maig f ebicDNA eece t crmme (15) elmated t btyce te DMD gee ad bee ced it became ibe t examie te

gee ere ad te tei rdct mre directy eeig ce tibe fcti

Expeon of he DMD Gene

Nrte bt aayi wit te iitia cDNA ce cfrmed tat te geewa exreed i feta ad adt ma keeta mce bt t i kifibrbat r ctred mybat ( 1 2 100). Frter tdie ave reveaed tatte gee i exreed i mygeic ce ctre y aer te frmati fmticeated mytbe (89, 06) ggetg tat te gee rdct imrtat after te et f termia differetiati

ig te mre eitive NAae rtecti aay meage a beedetected i rat (0) ad me (1) keeta mce, cardiac mce adbrai a we a i mticeated mytbe frm a me mygeic ce iead frm rimary ctre f ewb rat mce (0) Amificati f

mNA by te ymerae cai reaci a ved t be a very eitiveaay ad a detected dytri meage i keeta eart ad mtmce eer amt (arximatey I% f te amt i mce) i brai,kidey g ad aceta ad trace mt (e ta 0 1% f te amti keeta mce) i iver ee ad ctred fibrbat r ymbat(a)

I r w abratry te ed f te gee a bee iated i a cmidce ad a bce ctaiig te tative rmter a bee teted frrmter activity i mce ce Exrei wa ee i trafected

mytbe i a tadard AT aay fr rmter activity (1Te eve f fegt meage i greaty redced r abet i atietmce ( wever i me tiet at eat meage ca be detectedby i it ybridiati wit a rbe frm te ed f te gee (06) Timeage remaby defective aet aticay revaet ardte cei f regeeratig mce fiber (06) citet wit it exreii fed mytbe i ctre.

Dophn Sucue Deduced fom cDNA Sequence

Te etire ma DNA ad rti f te me cDNA fr te gee avebee eeced ( 6 ) Te ma eqece redict a 7 kdrtei 6 ami acid i egt (Figre ) t DNA ad rteeqece re igy cerved betwee me ad ma Te dedcedami acid eqece f te rte dytri redict a rtei f at eat

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6 8 WORTO & THOMSO

fou domains The N-temina doma shows stong seuene homology inmino acis 4 to 240 to the ctinbining omin of chicken lphctinin( 83 The seon an laest oman, amino ais 278 to 3080, isplas a

wek epet patte ey simila to the epeats found in aphtinin andspetin (3a 83 The 109 amino id epeat unit of dystophin an beaigned with the 106 amino aid consensus epeat of spectin suggesting tple helia sttue fo dstophin simil to tht popose fo spetn(32a , 83 The 26 epeat units an be seen in the shemati o Fiue ethe fist 20 eons boundaies of the epeat units oespond to eon-intonbodes suggesting tht eon dupliction s the eolutionay stategy foengthening the potein by ading epeat unts The epet domain pobablopts shape (Figue s it does in lph-ctinin n spetin n theself-assemby of these two poteins into anti-paallel dimes suests a simiadimeization fo dystophin (83

The thid omain amino aids 3080 to 3360 is ysteine-ih an isfoowed by the -temnal doman of 35 amino ads The th domanbes seuence simility to the teminl omain of Dicostelium phatn n (but not hen alphatinn whh ontns two + binng sitesin the fom of EFhands (Fiue 4 The teminal omain beas nosimilaity to any known potein

The featues of dystophn ae theefoe stongly suggestie of a ongolie moleule that pehaps bns ytoseletl tn n peoms sttul oe in the cell (8.

Loazaton of Dystrohn n th Mus C

The seuene of theDMD DN pedte a potein of 47 kd Homan andolleagues (68 hae deteted a otei of appoimately 400 kd on Westeblots of mouse skeetal musle poteins The ntibodes used fo the Westeblot analysis wee dieted aginst a denatued fusion potein made in col

fom a gene onsisting of the bateil trp gene fuse to DN cones fomthe mouse euialent of the DMD lous hese anti-dystophin antibodiesdetecte high molecula weight potein in human and mouse skeetal andcaa muscle lesse amounts n smooth musle, an smal amounts inbin Dystophin ws not detetabe in the muscle potens of two aectebos

ubellula oalization of ystophin to the tads of skeetal musle bWeste bot anaysis of ftionated mouse musle w as epote by Hoffmannd cowokes (6. Dystophn opuifed with the a+ elease hanne

poten (anoine eepto and the (a+ + Mg+ TPase in the heymicosoml fction contining the s The td junction consists otansese tubules (naginations of the saolemma ntedgitated betweentwo teminal istea of the sacopami eticuum (R. The tiad untion

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MAR TRO T 6

s t st t polazaton snal fom t moto nuon atats tlas o a om th S to ntat ms ontaton oalzaton ofystopn to th tas sust tat t mt pay a ol n anon t

tas to t myofblla ytosklton an tat ts loss tou mutaton mtsupt Ca omostass 7Sts by ZbzykaGa n o on laboatoy n ollaboaton t

Kapat at th Montal Nuoloal Isttut ha l to somat ntonluson 138 Antbos ppa aanst synttc ppt an natpotnA fson potns fom human DMD DNA lons asoonz a -k msl pon at s absn o a boys 38.Mosop loalzaton of ystophn sn nt anbotn basmmnopoas o mmnoosn on yostat sons of han

musl as a a stann patt onfn to t saolmma of myofbs No ntalua stann as bn sn n tanss o oss stonsnatn a u amount of mmunoat potn n t tas Snths son potn antbos t at th sam poon of th potnas thos of Homan an sn sma suts a obtan t pptantbos t aanst amno a suns fom Kun'sonal DNA lon 38 t ytoloal ata a n som samntt t bohmal fatonaton ata Sn T tubuls a nanatons ofth ufa mmban t posbl that som ytophn s loat alon t tubua systm atou t majo onntaton appas to b at t outmmban A smla mmban loalzaton of ystopn as bn at antboy t aanst anot syntt ppt fom Knk's DNA sun an lon mosopy mmunooabl antboy has sust tat t majo stbuton of ystopn s ont ytoplasm a o t musl pasma mmban ( 1 a T ytooaln f ot ssts that ystophn pays a sttal ol at tsaolmma an that Dhnn an msla ystophy a th slt

of mus mmban nstallty lat to stophn nsuny Tloazaton of ystopn to a mmban omponnt an ts putat funtonof stabn t mmban &) a ntly onsstnt th molo a a ytoskta potn Wth t potn passs thoh th mmban o attahs to som oth tansmmban ptn a mat fo spuaton an pmntaton

Pahogeness of he Dsease

aly DMD an BMD psn a sptm o sas sln om

ytphn nsny Wst bo analyss o potn om msl bopss o patnts th aos nomsl sos has al thatystophn s not ttab n most s DMD patnts s psnt n loamount n som patnts t an ntmat pnotyp an s psnt but

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H M H 62

If dx mce ae mtat te DMD ee cofm te aldt of te model te te easo fo te mld ad taset peotpe te mosema old a mpotat cle to destad te seet of te ma

dsease e possblt s tat te lack of dstop s most tamatc lae calibe mscle fibes wee te mecacal stai pe t sface aea ste eatest (76 I mce wee few fbes ow to a damete eate ta22 m te effects of te dsease e mmzed (6 s s cosstetwt te fact tat DD patets te mscles wit small calbe fbes(etaocla laeal ae spaed fom te semetal ecoss ad affected bos wit owt omoe eficiec te cose of te disease iscosdeabl mlde (16 ast mscle fbes appea to be pefeetallaffected ( 1 2 alto te bolocal mplcatos of ts ae ot et clea

Aote amal model tat ma mke t possble to test te elatospbetwee mscle fbe sze ad seet of dsease s te Xlked mscladstop of te do s disode eembles DD cliicall ad appeas toole a defcec te do dstop ee e oppott totasfe te ee to lae ad smalle beeds of dos sold pode edecefo o aast te fbe sze model ad te e exstece of te do modelpodes oppottes fo teapetc tals tat ma poe to be of mpoace fo te ma diease

ALICA TIONS O RVRS NTICS TO OTRDISASS

ee ae ma eetc dsodes fo wc te potei alteed b te mtatois completel kow ad otes fo wc tee s speclato bt o exactkowlede of te pote otos ee sdomes ad X-lked dsodessee female caes of Xatosome taslocatos wc ae bee ialable te eese eetic appoac to mscla dstop ae also of poeo potetial ale te seac fo te podcts of te omal alleles of otema dsease ees.

onguous ene ndomes

Te ae seeal dsmopic sdmes eac wt a wide spectm ofcliical epessio wic some bt ot all patiets ae a specfcctoeetc abomalt Tese icle te W A comple (Wilms tmoaiidia eitoia tact malfomatios oadoblastoma, ad metal

etadato ecwtWedema sdome Geoe sdome aeGiedo sdome Mlle-ee sdome ad etobastoma A deletoo ote mtatoal eet aecti a small semet of DNA cota ambe of adacet bt fctoal depedet ees i s tot to deetese dsodes ad epla te aable epesso ad ela eetc

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6 ORTON & TOMPSON

pae ( 3 Anal of e gene deleed o defece n ee ndomewl be efl n e ongong e o ndeand noma deelopmen ( 3

e comple penope aocae w p2l deleon no onl led o

conng of e DD gene b ae ao poded ng no e genecoganzaon of one of e f eended comoomal egmen o be analzed in dep Wiin i gene cle, e gene a i abnoma in concganomao deae GD a alo been cloned (0 ng pobe deed fom egon of p a wee aen fom e DNA of paen BB (86 98. mla appoace ae led o e clonng of e enoblaoma geneon comoome 3 ( 88 and ae eng applied o oe dieae gene

Te aceemen of a deaed map and compee eence ana of eman genome a pojec a a cag e magnaon of man genec and n pe of ome epcm, wll ndobedl be ped becae of mplcaon bo fo bac cence and fo cncal medcne (71 n amalle cale, e abili o analze DNA ample o loo o gene eponibe fo common geneic defec a oio clinical applicaion. Te ecnie of mappng and cloning deeloped fo e anai of congo genendome ae lie o find wide applcaion in geneic medicine.

X/autosoe Tanslocations

o o e man pbied eample o /aoome anlocaion aociaed wi fl manifeaion of an ned ai in a female ae cae of DDo D (7 eeal oe dode ae been mapped o egon of e comoome b mean of aoome anlocaon: Aaog ndme,Acad ndome, andc ecodemal dplaa, Hne ndme, nconnena pgmen, Lowe ndome, ene ndome and e TKCRocoll elod, cpocidm enal dplaa ndome (30 63 7Higeoion comoome anali i eefoe indicaed fo an femaemanfeng an ned a, a e denfcaon and anal of a balanced

aoome anocaon can bo epan e clncal epeon and ndcaee gene' pobable map poonaoome anocaon aocaed wi ned dieae, le comple

deleon ndome ae epeimen of nae a can be ed no onl omap deae oc on e comoome b ao o pode e age focomoome wang and mappng n an aemp o nd and cone e gene

In e few ea ince e new genec began o be applied o DD man ofe eoecal and pacca pobem aocaed w e deae ae beenoled, o a ea ae become open o olon. Femoe, appea aanwe o e Dcenne poblem ma eend beond e deae elf and

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DUHEE MUSLAR DSROH GEES

r nsnng n g s s n s n n r sry ss f s n ngr n r grs

iteature ited

ahaa K. shua S, shgo skahara . Shaa Y et a! 1988nosaning o skeleal an caacmscle srface membrane wh antboyagans cenne ca ysphypee Nt 33386-63

a . Bakker E Bonen E J, e LangeL. F . , Veenea, . MajoorKrakaer, e a 1 986. NA probe analyss orcare eecon an penaal agnosso chenne uscla ysophy asana agnosc rocee .t 23573-80

2. Bakker E. , Van Broeckhoven C , Bonen . J Van e Vooren, M. J,Veenea e a 1 987. Gelineosacs an chenne scla ystrophy aons Nt 32955-6

3 . Barley, J A Pal, S . avenport S Golsen . Pckens, J 1986 chenne muscla ysophy glyceroknase efcency an aenal nfcency assocae wh Xp21 nesa

eleon 108:189-924. Benha, F J, ogknson S , aves,K. E , 984 A glyceralehye3hoshate ehyrogenase pseogene on heshor a o he huan X choosomesenes a ulgene aly. EO 3:263540

4a. Berelson, C J Barley, J A Monaco, A. P. ColeFeener, c , schbeck K, Knkel, M 986Localsaon f Xp21 moc echangepns n chene usa ysrophyfales J t 2353-37

4b BjergnNelsen, L Jacobsen, B.B Nelsen M, abo A. 1983Xatosoe ansocaon n a gr whscar ysrohy C t 23242

5 BjergnNelsen , L , Nesen, M ,984. es synrome an uchennemscla ystrophy n a gl wh anXuosome nslocon. 27173-177

6. Borug S E Ray P N Gonale .L., Schckel R. , Syvese, J Eoon R. G 7. Moecuar nyss of constuonl Xtosome

ransocaon n a feae wh musclarysrophy 3: 60-47 Booln R , a Slva, . M . Che

R. VannaMorgane A. M.at, M. 986 Brief Clnical Repor

uchenne sca ysophy n a gwth a 45X/46XX47XXX choosoe conston m . . t.25239-43

8. By Y Bce V . 986. Cygenec heteogeneiy o tans loaonsassocae wh uchenne scarystrhy C t 291085

9. Boy Y Cockbu o S. Mno E. Van Oen G J Gilla BAaa N FegsonSith M Cag., 1988. Mapng of welve X2translocaon breakponts wh espect othe locus for chenne scla yophy Cytt. C t, sbie

0. Boy Y Mno Ray P oonR, Monaco, e a 198 Moeculaheerogeneiy o tansocaons associate wh scla yrohy C t 3 26572

Brockorff, N Cross, G. S CavannaJ . S. Fse, E M . c , yn, M . F ea, 1987 he mappng of a NA o

the huan Xlinke uchenne scarysrophy gene o he oe X chrosoe. Nt 328:166-68

1 2 Brghes, A M , Logan c , , XBelfall B , Woon R G . Ray, P N,987 A NA cone o the chenneBecke mscu ysophy gene Nt 32843437

13 Bureser, M Lehach 1 986.Longrange rescon a aroun hechnne sca ysrophy gene Nture 348-8

4. Breser, M. Monaco A. P, Gil

ar E F., Vn Ommen G. J B,Afaa, N. A , et a, 1988 A 10 egabase hyscal map f han Xp21 nclung he chenne sla ystphy gene m, 2189202

15 B Povey S Boy Y Muno A , We L e a 1 986 chennecl ysophy in on o onoygoc wn gls. t. 23494-500

6. ank, N. rla, B. vaar ,7 ystophe muscae e chenne ch ez ne ette e Pote e

une tansocaon (X;32 ;q 3 enovo . t 22:35-397 . aba S a S G.

Reevs A A. Mns, L J, Sephenson A, et 987 Regona

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62 WOTO & OMO

oazaton o th mrn Dnnmsar dystroy n on mos romosom. . . . :67-78

8 Chambrn J S. arman J. AMzny D. M Gbbs R . A Ranr J a 988 . xrsson o t mrnDnn msar dystrohy n nms and bran. 23914117

18a. Chambran J. Ranr . arman J A. Far N. J GbbsR t a. 988 Anayss o Dn-n msar dystroy n mtatons nm and hmans n Cur dur Bg f us Dvp. LA mos on Morand Car Booy N sVom Aan R. Lss n. Nrk N 19 Cy J. Marns F Dtrax B Van Ommn G J Lambrt M t a988 Don roma to 68os (L rob st n a boy Dhnn msar dysroy yroknas dny and adrna hyoasa Hu. . 782227

19a Cy aan J Mar Gatron S . ahn A 988 ransrton o t man dystrohn n nman ms and nonms tsss.Nur 3338588.

2. Chy J Marns F. L Mar B . a 1 98 D noo DNA mrodtonn T syndom andDnn msar p Hu 741939

2 1 Cark A Robrts S H . Thomas N.S . htd A ams J Har-r . , 98. Dhnn msardysroy th drna nsny ndyro knas dny h rsoton yon anayss t moar bhma and na stds d. . 2358

22 Co C. G Coyn A . Hart . A Shrdan R. akr A t a 1rnata tstn or Dhnn and B-kr mar dysohy. :225

Coo, J nand N J StdmanH. Vantn B A Homan . . t a 1988 . T homoo o hDhnn os s d n Xnkdmsar dystroy o dos. Nur334154

24. Cross G S Sr A Rosntha A . ost M mt T J drds

. t a 1987. Dtons o ta andad m DNA n Dhnn andBkr msar dystrohy atns.B J 63-83

25 Dan G. A Barban G 98.

Dhnn msar dystohyFrqn-y o sorad ass. Hu. 722

. Darras B . ran 987 Aarta don o h msar dysroy n transmtd t by an nad ma Nur 3295558

27 . Darrs B T Fran V 1988.Myoaty n om yro knasdny atns s d to 3 ' donso t dystrohn n J Hu., 3230

28 Darras B. . Harr . rankV 987 rnata danoss and d-ton o arrrs h DNA robs nDhnns msar dystroy. Nw.. J d. 3 98592

29. Darras B. . on M nk L.M , 988 Drt mhodor rnata danoss and arrr dt-ton n Dhnn/Bkr msar dys-trohy sn th nr dysronDNA. . J d. . 973

3. Das . Mand JL ssn-bah J. Fos M 1987. Rort oh ommt on th t onston o th X and Y hromosoms. . 77315

3a Das . attrso M N n-rk . J. B M. V . Soan H R. a. 988 Fn man o yroknas dny and onna adrnayoas thn X[ on t short armo m X omosom . Jd 295575

31 Das . . arson . L Harr S Mrray J M O Brn T. t a1983. Lnka anayss o to ondDNA sqns ankn t Dnnmsr dysrhy os on th sortrm o hman X omosom.Nu ds Rs 23313

32 Da Smth T Bndy Rad A. Fn T a 1988.Md and sr msar dystrohyassoatd dons n p2 o tman X romosom. Md Gn25913

32a. Dason M D. D R 988 A[haAtnns and th DMD on onan strnk rats. -521591

33. Dn Dnnn J. T Bakkr . [nBrr E G. arson . L. VanOmmn G. J. B 987. Drt dt-on o mor han 5% o Dcnnmsc so mos b d

nrson s. Nur 32942. Dos H. Jnn C Mand[ J. L. romann . Moson J t a1985 raton anayss o a markrosd X2 1 2X2 1 3 n Dhn

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D MSAR DYSTROPY GTS 62

a ecke mucular oh fami-les Hm . 1

35 Duger D embe M eaoP Wifiel Daies K E Lake

Wams D Do M D 186 Deleio o he X chomoomedeeed b die DN ali i oeof wo urelaed o wi gceolkase defciec area oasaa Dcee mscla dsro t 188

6 Emae Zaca E ce 18 ue eece o X21locao o Dcee scla s-h DMD oc X alocaio i afemale wih DMD M. 266

Emer E 186 Mh Ml t tt ts ms. Eibug Ccill Liigoe

8 Eme A E 18 Duh Mu sph Ofor U Pe

Egel A 186 Dcee dso- I Mg e G Ege Q ker New Yok Mawill 1 8 28

scbeck K Rie W -cw D M eeoC J e a 86 Recombiaio wih

PER8 DXS6 i famiie wih Xlke muula doh L 21

1 orres M Coss G ee A GadeMedwi D u J Die , 8 Prfntial dion o -o Duee a ecker muculardsoes Nt 2682

2 orres M Cross G S omasN S T , He S Smi T J a 18 Effeie aeg for eaalreco o Dcee a ecemucua oh t 2 1 2

6 acke ape J Daa Cowa M Mcabe E R . ea 18 Cogeia adrea holaiaoa ad glceo kae eficiec Moleular geeic eiece fodeleio m . J Hum 212

ace U Ochs D DeMa-e acaoe ge ea 1 8 io X2 1 omoome eleio i a mle aociae wih ee-so of Dee muular o

choi gulomaou iee eiiigmeo a Mceod mem. J Hm. t 26

Fd, S ea R Rogej SWeibrg R Raaor J M e al186 A ma DNA egme wi

roerie of e gee a edioe oreioblaoma ad oeosarcoma N 266

6 ilard E 188 Molcua aasis

of Dcee mscar sr adohe X muaio usg coe DNAeuee hD hei i Glagow

ome M R Egel Dewa eeso A 77 ale oiacaio o Dcee do X-chomoome i oe of femae ideilw Ng 2

8 oodelow . N Daie K E Ro-es 18 Reo of e co-miee o e geec coso of eX a Y chomosomes ma eeMaig 8 gt. .

262 oodsi Malcolm RoersoM E embe M E 88 ervceeeriee uig DN ali fo ge-n pedn n Duchenn msudo M . 11

ra Mlis L J ee-so D A Cama V M 188Rcombiaio g e md adDmd loci o e moue X chomoomem I re

Geebg C R suie i ewbo males wi Dcee

mucula so deeced b eoaalceeig t 22522 eerg C R amero J L

Nigli M Wogema 8 DNudie i a famil wi Ducheemula deleo X2 m Hm. t 1128

Grimm 186 eck Dso IM ed G Egel e Qake New Yok Mawill

5 ammo R 18 roei se-ece o DMD gee s elae o ac-bdg doma of alaacii Cell

1 1 aper P 18 2 Caie deeio i

Duchee muca dyphy: -cal eme I Ds o thMt . e D L coa NewYok Wile 8216

6 a K Cole C Walker ogo S Joo L , e a 186 Tescreeg o Dcee sclar sro-h ae o bmicoscoc eeons. J M t. 2 62

5 a K odgo S Waker Coe C Joo L e a 18

DN deleios i mil ad seere e-ck mucular dro Hm t52818

58 eig R. emare C Madel Dadoo L mar L A P 18 Localiaio o e reio

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626 WOO & HOMPO

homoloos o te ucenne mscldstroph ocus on the mouse X cro-mosome Naur 32:160

5 Heg, R , Lemae, C , Mande, J L ,

187 A 230 k cosmd wk n heucenne muscua dstrop ene: de-ecton of conserved sequence and of possle deeton prone regon NuccAcids Rs 151242

60 Hejmnck, J F , Has, S G , Tsao,C C Wd P A, Cske C T186 Crre dagnoss of Ducennemusculr dsop sn restrctonfmen enth polmopsms Nu-rooy 355362

61 Hodson, S, Boswnke, Coe, c Wke A , uowz, V Ganata C

Meln, L Boow, M . 186 A lnk-e sud of meress musculdstop Hum nT 744016

62 H S, Wlker, A. le ,H K J L et a 87 Theppcton of lnae analss o geneccounsen n fmles t ucenne oecke muscul dsoph 1 MdGenet. 2412

63 Hodgson, S V , Nevle, , e W A e C Borow M , 185To cses of X/tosome tnsoctonn emles t nconnenta pmen

Hum Geet. 7123134 Hoffmn, P. B H elL M 87 Dsophn The protenpoduc of the chenne muscudstroph ocus C 5:128

65 Hoffma, P Fscheck, H wn, H M. MeR et a 188 sophn qult ndunt eemnes the clncal sevetof Duchenneecke Musclr Dstophes Nw E 1 Md 318136368

66 Hoffmn P , Hudeck M S ,

Rosene P A , Poln C M n-kel, L M . 188 Cell and fetpedstrbuon of dsropn C npess

67 Hoffmn P Knudson, C M Cmpel K P , Knke L M . 87Sucelular frctonaon of dstropno he trads of skelea mscle Naur0:75457

68 Hoffmn P Monco A P, Fen-er C C, Kunke, L M 187 Con-servon of e Duchenne musclrdsop gene n mce and humans

Scnc 238347506 Hofker, M H Bergen, A A ,Skastd, M . Bkker, , Frncke,U. et l 186 solaton of a andomcosmd cone, cX, whch defnes a newpolmophc ous DXS48 nea e

locs fo ucenne musc dsophHum nt 74:277

0 Hoe, M H, Wapenaar, M . Goo, N, Bakke, , Vn Ommen, G

. B , Peason, P L , 1 5 Iolaon ofproe detectng eston frmentength pomopsms fom X como-somespecfc lrres poenta use fordanoss of Duchenne musculr dso-ph Hum 70: 14856

70a Hle J A t A McP M, Maso, R Dunan, A M . V ,186 Xp2auosome tanslocaonsCin nt 21622

7 ood, L , unkple M. W ,Smth, M . 187 Atomaed DNAsequencng and analss of the man

genome nomc :2011272 Hu, X , Bues, A H M R, P N Thompson, M . W, Mph, E G,Woon, G , 1 88 Ptl n dup-c n Duchenne nd Bece musculadstophes M n 25:3676

3 Jacos, A un, Me, M, D 181 Duee ult DMD femle wth anXautosome trnsocao uhe ev-dence tt e MD ocs s t Xp2 1 Am um n 33131

74 M. M N , Fujk,K , . 8 Genec pdem-olog of uchenne musculr dstrophn Jpn Clssc seeaon anlssn pd 442532

7 Kapu, S H . V, De1p, K,oger, B, 8 Mee e l Xuosome tnsoconAm 1 Md nt 265030

76 Kt, G Capene, S 1 86 Sml-e elel musle be t suf-fer deleterous consequences of dstro-phc gene expesson Am Md

n 256535877 Kean, V M , McLeod, H L , Thompson, M W, a, P N, Verelen-Dumouln, C Worton, R G, 186Patel nhetnce of ansloctoncromosomes n a (X;21) ptent wt Xnked musculr dsp 1 MdnT 23:413

78 Kenwck, S Ptterson M Speer A Fsheck K Dves K 187Molecula analss of te chennemuscua dstrop reon usng pulsedfeld gel electropoess C 48:351

577 Kenwck, S J , Smth, T J , nnd,S, Colns, F, Dves K , 188Localston of the endpons of de-leons n e ' regon of e Ducenneen usng a sequene soaed

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CH MCAR TROH GTC 2

homoome ump. Nl Rs. 16:130517

80. Kgo H. M. Sz M., Thom, N S. . Hper, P S. 1984.

oitio of the eke muudyophy ee o the hot o h homoome y like to oed NAeue. Hm. G. 67:17

81. Klmut H. J., 1988. ee expeio.Pero ommuitio

82 Koei M om P erloC. . Moo A P, Feee, C. Kukel, LM 1987. Compee oig o thuhe muur dytrophy (MNA d peimi eom orizto o t M gee i orml deted idvidu Cll 5050917

83. Koeg, M Moo, A. P Kuke L.M. 1988. h omplte que odyophi pred o odhped ytokee ptei , 5398

84 Koh . PerkVe, M. A . Ymok L. M. Hug, WY Woo, R e 1987. Iherited deeio tuhee dytophy lou i ommle Lact 2 555

85 Kuk, L. M, Hetmlk F, Cky, C. T. , Sp A . , Moo, A P , . , 1 986. Ay o dlto NAom ptet wth ke d uh

muul dyophy Natur 322737786. Kukel L. M., Moo A. P Mddewoh, W., Oh, H. ., Ltt, S A1985 Spei lo o NA gmet et om he NA o mleptet wth X hmoome deeto.Po Nat. Aad Si. USA 82477882

86. Kukel M . , Ttrvhi , U Ehd M tt S. A, 1982 Regiolotio o the hum X o NAegmet loed om owotedhromoome. Nuli id R 10 155778

87 Lm T PkVe M A. ,lett R Che J c Ymok et 1987 Fmil ihete o S 64 deeo muo om heeoygou e J um 41 1 384

88 e W. H ook R . , Hog, F .,oug J Shew, J. Y Lee . Y1987 Hm eoom uepiy gene: log, idio duee. Si 235: 1 3999

89. Lev A. A., ee C C., Kuk L.M., row, R. , 1987 Expeo o

he uhe muul dytophyge i uud mul J Bo.Chm. 262: 1 5 81 720

90 LiehiG, S , g S , Hi,H Moe H 1987 Fmlil deetioi ke yp muul dyophy

withi he p eio. Hm. G. 7726768

91 . Ldeum R. H . , Clke, G. Pe,C. Moeff M. ughe . 1979

Muul dyrophy i oio fem ue uhou o hromoom hor . Md. G. 1638992

92. if M. Kie H. vie K.E. e l Chpell A. 1986. Cirdteo d pret dio i iked muu dyophy u reio gmet eh polymophm. JMd. . 23:5672

93. Ldl, M Kie . V Omme G. . . e Chple A1988 Miodeltio ptie wih X

liked muul dyrophy: moleulril oeo. Cl. . 33 :13139

9 Lidl, M Sito P, lChpele, A 198. Liked poymophi NA mke he predo oliked muul dyophy Hm G. 5131728

95 Mlhotr S. 1988 Pheoype orrelio Pol ommitio

96 Moo A. 0 tl, C. CoF c Kuk, L M. 1987.Lotio d log o Xp21 de

to kpo ioved i muudytophy. Hum. Gnt. 75212797. Moo, A P. ertelo C. . ih

iGllti S Mo H Kukl LM , 19 88 A plo o thpheotyp deee ewe ptete pil dltio of h Mou Gms I pre

98. Moo A P. relo C Mddewoth, W. Collet C. A, Addge, . Fihek, K H. letR PerkVe M. A. Roe A., Kukel L M., 1985. eo o

deletio pg he he muu dytphy ou ug ghty lkdNA egmt Nat 316845

99 Moo A P Kukel L. M 198 7 Ai lou for the uhee d ekemu dyophy gee Tnd Gnt33

100. Moo, A P Nv L CoetFeee, C. eeo C J. ui M., Kuke, L. M. 1986. Ioltio odide NA o portio o huhee muul dyophy gee Na 3236450

01 Moto N E Chu C S 1959Foml gee o muulr dyophy.m. Hum. G. 1 1 36079

102. Moe, H., 1984. uhee muudyophy: Phoeeti pe d eti prevetio. um. . 661740

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68 WORTO & TOMSO

103 Mosacciuolo M , omard Aamissa V , Danieli, G A Angein 187 Popuaon data on enign andsevere fos of X-nked muscuar

dystophy Hm Gn 75217201 04 Muay, I M, Davies, K E, Haer, PS Meredith L Mueler R Wilamson R, 182 nkage relatonshpof a cloned DNA sequence on the shortarm of he X chromosome to Duchennemuscuar dysophy Nar 3006971

10a Nazi, 0 Hanai, , cki, Mtsudome A 185 Duchennemuscuar dystrophy n a female wth anX-autosome ransocation in Nr2543236

0 Nevin, N Hughes A E. alell,

M im, H K 186 Duhennemuscular dysrophy n a female wh atranslocation involvng Xp21 J MdGn 23:17173

105 Nude, , Rozyk K affe, D,1 88 Th putave Duchenne musculdystophy gene is expressed in differentated myogenc cell culres and n therain Nar 331635

06 Oronzi-Sco! M , Syvester Heiman-Paterson, , Shi -, Fieles,W Stedman, H Burghes, A RayP Worton R Fishek, K H,1988 Duchenne muscuar dysophygene epression in nomal and diseasedhuman musce n 239:141820

07 Pena S D I Karpati G arpenterS Fser F c 1987 he clinicalconsequences of X-chomosome inactivaion: Duhenne muscua dysrophy in one of monoygotic twins JNr i 79337

107a erez-Vdal M Grau, E. SVinas P Bayona V RusteinP 183 Dysrofa muscuar ipoDuchenne en una hemra con unatranslocacion euilirada X/6 RvNr (Barcelona) 1 1 1 5558

108 Ray N Belfal, B Duff C ogan Kean V , e a, 985 onng of the reakpoint of an X;21translocaion associated wih Duchennemuscula dystphy Nar 31867275

08a Riei, M M , Melagno, M ,Schmdt B Brnon D Gaai AA, Hackel 1986 Duchenne muscular dystophy in a gir with an X15)ranslocation m J Md Gn 25:231236

109 Rowland, 1980 Bochemity of

muscle memranes in Duchenne muscular dysophy M Nrv 3320

0 Royer-okora B Kunkel L M ,Monaco A , Goff S c Newurger E et a 1986 loning the gene

for an inhered human disorder-chroncgranulomaous disease-on the asis of itschromosomal locaton Nar 3223238

l l Russo, A , Baujani G Mostacciuoo, M L Hemann, F H Spiegler W e a 187 Sporadic cases inDuchenne muscular dystophy-A reapprasal through segregaton analyss of988 sships Hm Gn 76230-235

a Saio, F , Goto , Kakiniema H Nakamura F, Murayma, S et a,185 Hgh resolution anding sudy ofan / ransocaton n a femae wthDuchenne muscuar dystophy HmGn 71:370371

1 2 Schcucrrandt, G undin, A v

gren T Moier W 1986 Screeningfor Duchenne muscular dysrophy animpoved screening test for creatnekinase and is applicaion in an infantscreening pgram M Nrv1 123

1 1 3 Schmickel R D 186 ontiguousgene syndomes A component ofrecognizale syndromes J Pdiari109:2311

1 1 Smih I Wilson, , Kenck, S Foest S M, Speer, A, e a187 soaion of a conseed sequencedeleed in Duchenne muscular dystophypaiens Ni id R 15:21677

1 15 Sedman, H Bowning K Oliver N ,OnziScott M Fscheck K et a1988 Neulin cDNAs detect a 25 kioase transcrp in skeeal musce andlocalize o human chromosome twoGnm 217

1 16 Sugita H , Arahata, K , shiguo, Suha sukahara et a 198 8Negave Immunostaining of Duchennemuscular dysrophy DMD and mdmuscle surace memrane wh anodyagaint yntheti peptide ragmen predicted fm DMD DNA Pr Japanad 6:373

1 17 Suga, H , Nonaka I Itoh Y Asakura A Hu D H, et a, 187 Isneulin the poduct o he Duchennemusculr dysophy gene? Pr Japanad 631010

1 1 8 Thomas N S T Ray, N WortonR G Harper S 1986 Moleculardeeion anaysis in Duchenne musculadysophy J Md Gn 23509--5

1 1 hompson M W Ray P N Belfall B Duff C ogan c 1986 inkageanalysis of polymophisms within theDNA fragment X cloned fom thereakpoint of n X21 translocationassociated with X inked muscuardysrophy J Md Gn :

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DUCHENNE MUSCULAR DYSTROPHY GENEIS 629

120. Va Omm G eelon G B D Du . TBer et 97 em m f te Duee muu

dystrophy DD g: Isolio d of 66 68) ta ramker. nm 9-6

1 . V Omme G B Ver . M H Hoe, M H Moao A. P. Kuk M. a 96. A yam of 4 mo b aod te Du mu dytpy e tum Xrmm. e 79-504

122. V-umo H . Fd M . D Myer R Ltre H dr . t 1 9 p f X

ed muu dytry fmd o anoao vov 2 adoadom avao of h ormaX mme um Gene 67 - 9

W M C Kvt , oL. A. Ba D Due T a 197 Hybd mdado o w t ufm te ' re f t DMD eytnt nt.

124. Waaa M. Kv T. Ha K.A B D D

T , et 9. A deet tt teDuee muur dytpy eenm 2 1 0 0

24a. Wak S Hoffma P Sayt H. Ku L M 9 Immueer mp zt ytp mye Nue33363866

. Wbs Sbt L Hays AP Bu H M 19 t mue fber r efety ffetd Du muu ytrpy 52:5013

6 x D Coo A oa Byd At D A et 96.Du muu dyy du fm a 2 do dab yDNA ay d f ytmetryum Get 717-

17 m W R Tm M W oo E 98. Cmx reo aay ad om-ad c am o Dumuu dytry. m. Me. nt 4 5

8 W A 988 Th moat o Dh mua dyoy te b e ? Tnn 7

29 W D S . Zvi M P Aoa Svat G . t 97. Nb h dv pdut Due muur dyty? Newn. . 361070

30. Wood S. MGvay . 19 Gma moam D madyty. Hum n 7-

. W R. G 197. Meu yss f Dh ad B msadyohy. 7762

. Woo R G. ug A H. M . 97. Meur et f Due

Be muu ytpe. Intt. R Nb. 297533. Woo R . Dff yv .

me R H F9 Due muu dyty v octo o e DMD x o booma RA n22444749

. Yud N . K K. 198 No dfferee mutt te f Duema dyoy . . nt7 061

\ Yat R W Aaa N A

me D. M erumt MA HumPetuez et 986. EmryDfu muu ythy oaao o q273 q ofmed by e o t ftr VIIIee Me. Genet. 7-9

Zaz M. B Dumuu dyty a whowh homo dy: A i yarfup. m Me. Genet 677

137 az M. VaaMoa A M.amo P Dam A. . 9

aoao 6) a ma wDue muur dytry Im h t f DD o . . nt 144247

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Dmd Seminar Shptsk

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