ORIGINAL INVESTIGATION

Jamil Ahmad Æ Shaheen N. Khan Æ Shahid Y. Khan

Khushnooda Ramzan Æ Saima Riazuddin

Zubair M. Ahmed Æ Edward R. Wilcox

Thomas B. Friedman Æ Sheikh Riazuddin

DFNB48, a new nonsyndromic recessive deafness locus, mapsto chromosome 15q23-q25.1

Received: 5 October 2004 / Accepted: 11 December 2004 / Published online: 12 February 2005� Springer-Verlag 2005

Abstract Nonsyndromic deafness locus (DFNB48)segregating as an autosomal recessive trait has beenmapped to the long arm of chromosome 15 in bandsq23-q25.1 in five large Pakistani families. The deafnessphenotype in one of these five families (PKDF245) islinked to D15S1005 with a lod score of 8.6 at h=0, andthere is a critical linkage interval of approximately 7 cMon the Marshfield human genetic map, bounded bymicrosatellite markers D15S216 (70.73 cM) andD15S1041 (77.69 cM). MYO9A, NR2E3, BBS4, andTMC3 are among the candidate genes in the DFNB48region. The identification of another novel nonsyndro-mic recessive deafness locus demonstrates the high de-gree of locus heterogeneity for hearing impairment,particularly in the Pakistani population.

Introduction

Autosomal recessive nonsyndromic deafness is geneti-cally heterogeneous and is the most common form ofinherited hearing loss. More than 40 loci have beenmapped, and 20 of these genes have been identified(Hereditary Hearing Loss Homepage, http://www.uia.ac.be/dnalab/hhh/). Many of these deafness

loci have been mapped either in endogamous popula-tions or in families with children of consanguineousmarriages (Friedman and Griffith 2003). As a conse-quence of the unique socio-cultural practices in thepopulation of Pakistan, approximately 60% of mar-riages are consanguineous, of which more than 80% arebetween first cousins (Hussain and Bittles 1998). Theselarge consanguineous families are a powerful resourcefor genetic linkage studies of recessively inherited dis-orders. In this communication, we report a novel deaf-ness locus DFNB48 genetically mapped with the aid offive consanguineous families from remote areas of SindhProvince in Pakistan. This locus resides in an interval ofapproximately 7 cM on chromosome 15q23-q25.1.

Materials and methods

Patients

After approval from our Institutional Review Board(IRB) in Pakistan (FWA00001758) and from the NID-CD/NINDS IRB at the National Institutes of Health,USA (OH-93-N-016), written informed consent wasobtained from all participating subjects. Pure toneaudiometry by using air and bone conduction (fre-quencies of 250–8,000 Hz) was performed on many af-fected and unaffected members of these families.Vestibular function, evaluated by using the tandem gaitand Romberg tests, was normal in ten affected individ-uals (two from each family). Clinical examination andfundoscopy of affected individuals ruled out syndromicforms of deafness.

DNA isolation, genotyping, and linkage analysis

Genomic DNA was extracted from blood samplesobtained from all participating family members by a

J. Ahmad Æ S. N. Khan Æ S. Y. KhanK. Ramzan Æ S. Riazuddin (&)National Centre of Excellence in Molecular Biology,University of the Punjab, 87-West Canal Bank Road,Thokar Niaz Baig, Lahore, 53700, PakistanE-mail: riaz@lhr.comsats.net.pkTel.: +92-42-5421235/+92-42-5421350Fax: +92-42-5421316

S. Riazuddin Æ Z. M. Ahmed Æ E. R. WilcoxT. B. FriedmanSection on Human Genetics, Laboratory of Molecular Genetics,National Institute of Deafness and OtherCommunication Disorders,National Institute of Health, Rockville, MD 20850, USA

Hum Genet (2005) 116: 407–412DOI 10.1007/s00439-004-1247-y

standard protocol (Grimberg et al. 1989) and quanti-fied spectrophotometrically. All the reported nonsyn-dromic loci were genotyped before a genome-widesearch was undertaken by using 388 fluorescentlylabeled microsatellite markers at an average spacing of10 cM (ABI, Prism 1, Linkage mapping set 2.5,Applied Biosystems). Thermal cycling was performedwith an initial activation step at 95�C for 5 min,followed by 30 cycles of denaturation at 94�C for 30 s,annealing at 54�C for 45 s, and extension at 65�C for2 min, with a final extension at 72�C for 10 min. Analiquot of 2 ll of this polymerase chain reactionproduct together with 11.8 ll formamide and 0.2 llLIZ size standard (Applied Biosystems) was pooled forgenotyping in an ABI Prism 3100 Genetic Analyzer.

The alleles were assigned by means of Genescan andGenotyper software (Applied Biosystems).

Lod score calculations

For linkage analysis, the Marshfield genetic map (http://research.marshfieldclinic.org/) was consulted for markerorder and map distances. Lod scores were calculated byusing MLINK (Schaffer 1996). The disease was coded asfully penetrant, and the disease allele frequency was setat 0.001. Meiotic recombination frequencies were as-sumed to be equal for males and females. The allelefrequencies of microsatellite markers were determinedby genotyping 90 random unaffected individuals fromthe Pakistani population.

Nomenclature

The DFNB48 locus acronym was provided by the Hu-man Genome Organization (HUGO) NomenclatureCommittee. The gene symbols used in this article alsofollow the recommendations of the HUGO GeneNomenclature Committee (Povey et al. 2001).

Fig. 1 Pedigree of family PKDF245 with haplotypes of markers at15q23-q25.1. Affected individuals V:10, V:11, VI:6, VII:5, VII:7,VII:9, VII:10, and VII:11 provided the proximal recombinationbreakpoint at marker D15S216 (70.73 cM). Distal recombinationwas provided by affected individual VII:7 at marker D15S1041(77.69 cM). Therefore, DFNB48 maps to a 7-cM interval delimitedby markers D15S216 and D15S1041. The genetic distances inparentheses are from the Marshfield human genetic map

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Results

The pedigrees of five Pakistani families segregatinghearing loss are presented in Figs. 1, 2. Affected indi-viduals had bilateral profound congenital hearing loss(Fig. 3) segregating as an autosomal recessive trait(Figs. 1, 2). Linkage was first detected with markerD15S204 (71.82 cM) in all affected individuals of familyPKDF245 (Fig. 1), suggesting a novel deafness locusDFNB48. In order to confirm this linkage and to fine-map the genetic interval, 11 additional short tandemrepeat (STR) polymorphic markers (D15S1025,D15S216, D15S650, D15S977, D15S967, D15S1026,D15S973, D15S1027, D15S1005, D15S1041, D15S175)were genotyped. A maximum two point lod score of8.6 at h=0 was observed for marker D15S1005 in familyPKDF245 (Table 1).

Haplotype analysis revealed recombination eventsbetween D15S216 (70.73 cM) and D15S650 (70.73 cM)in affected individuals (V:10, V:11, VI:6, VII:5, VII:7,VII:9, VII:10, and VII:11 from PKDF245, defining thecentromeric boundary of DFNB48 (Fig. 1). The telo-meric boundary of DFNB48 was determined by arecombination event between D15S1005 (75.27 cM) andD15S1041 (77.69 cM) in individual VII:7 (Figs. 1, 4).

Genome-wide linkage analysis revealed two addi-tional families (PKDF270 and PKDF203) segregatingnonsyndromic deafness linked to markers at chromo-some 15 in bands q23-q25.1 (Figs. 2, 4). The affectedindividuals of family PKDF270 have the same haplotypeas observed in family PKDF245. STR markers in the

DFNB48 region were then used to screen 350 Pakistanifamilies segregating recessive deafness, and two addi-tional families (PKDF232 and PKDF356) were found tobe linked to this locus (Figs. 2, 4).

Discussion

We have mapped a novel locus for profound nonsyn-dromic congenital deafness segregating as an autosomalrecessive trait in five consanguineous Pakistani families.The locus was designated DFNB48 and resides in a 7-cM

Fig. 2 Pedigrees of four additional families PKDF270, PKDF203,PKDF356, and PKDF232 in which nonsyndromic recessiveprofound congenital deafness segregates with DFNB48-linkedmarkers

Fig. 3 Representative pure tone air conduction audiograms of anormal hearing person VII:6 (top, 15 years) and an affectedindividual VII:5 (bottom, 10 years) of family PKDF245. Theobserved threshold in all deaf subjects showed profound hearingloss (open circles right ear, crosses left ear)

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interval on chromosome 15 in bands q23-q25.1. Basedon our screening of 350 Pakistani families segregating ahearing loss phenotype, we estimate that mutant alleles

of DFNB48 are responsible for approximately 1.5% ofnonsyndromic congenital profound hearing loss amongthe families that we have ascertained in Pakistan. Thehaplotype of markers in the DFNB48 interval for twofamilies (PKDF245 and PKDF270) are the same. Thismay reflect a founder mutation, although these twofamilies are unaware of any common ancestors. Theother three families (PKDF203, PKDF232, PKDF356)have unique DFNB48 linked haplotypes, which mayharbor different alleles of the DFNB48 gene. More thanone gene may also be present in the DFNB48 interval inwhich mutations are associated with deafness. To ourknowledge, a deaf mouse model for DFNB48 is notavailable.

Campbell et al. (1997) have reported the nonsyn-dromic deafness locus DFNB16 on 15q21-22, which isdelimited by marker D15S994 (40.25 cM) and D15S155(52.33 cM). The region linked to deafness in our families

Table 1 Maximum two pointlod scores for five DFNB48families

Markers Marshfield mapposition (cM)

Lod score at h=0

PKDF245 PKDF356 PKDF232 PKDF270 PKDF203

D15S153 62.4 ¥ �10.68 ¥ ¥ ¥D15S983 66.9 ¥ ¥ ¥ ¥ �4.34D15S988 66.9 ¥ ¥ �2.47 ¥ ¥D15S1025 69.46 �0.62 1.73 �1.53 ¥ 2.63D15S216 70.73 0.55 2.55 1.21 ¥ ¥D15S650 70.73 4.34 3.80 0.06 �1.49 ¥D15S977 70.73 3.86 2.47 1.29 2.74 3.64D15S967 71.82 6.59 3.57 0.86 4.87 4.44D15S204 71.82 6.66 2.00 2.38 3.06 4.11D15S1026 72.37 7.25 3.76 1.10 3.75 4.23D15S973 73.52 4.98 2.00 2.37 4.29 1.76D15S1027 74.69 5.14 4.73 2.39 4.32 1.46D15S1005 75.27 8.64 5.19 2.56 3.55 3.85D15S1041 77.69 7.11 3.64 1.99 3.47 3.41D15S205 78.92 ¥ ¥ �1.53 ¥ 3.90D15S175 78.92 ¥ ¥ ¥ 2.56 ¥D15S979 83.4 ¥ ¥ ¥ ¥ 2.97

Fig. 4 Schematic representation of DFNB48 linkage on chromo-some 15q23-q25.1 in Pakistani families (filled circles STR markers,cross meiotic recombination, solid vertical lines chromosomalintervals in which markers are homozygous for affected membersof each of the five families). Haplotype analysis revealed recom-bination events between D15S216 (70.73 cM) and D15S650(70.73 cM) and between D15S1005 (75.27 cM) and D15S1041(77.69 cM) in family PKDF245. The affected individuals of familyPKDF270 have the same haplotype as observed in familyPKDF245. In family PKDF203, a proximal recombination waspresent between markers D15S988 (66.9 cM) and D15S1000(67.85 cM), defining the proximal boundary, whereas the distalrecombination was present between markers D15S205 (78.92 cM)and D15S979 (83.4 cM). Affected individuals in family PKDF356have homozygosity starting at D15S988 (66.9 cM), and a distalmeiotic recombination break point was present at D15S205(78.92 cM). Family PKDF232 has an interval of homozygosity ofinformative STR markers of nearly 9 cM, with a proximalboundary at 69.46 cM. The linked region for DFNB48 is therefore7 cM and is delimited by D15S216 (70.73 cM) and D15S1041(77.69 cM) defined by family PKDF245. There are 65 annotatedDFNB48 candidate genes between these two markers of whichNR2E3, MYO9A, BBS4, and TMC3 (bold) are discussed

b

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does not overlap with the position of DFNB16, whichhas been identified as STRC (Campbell et al. 1997;Verpy et al. 2001), thus distinguishing DFNB48 as aunique locus. Autosomal dominant nonsyndromichearing loss, DFNA30, delimited by markers D15S151(82.28 cM) and D15S130 (100.59 cM) is also present onchromosome 15q25-q26 and has been mapped in a four-generation Italian family in which members have pro-gressive hearing loss (Mangino et al. 2001). The criticalregion of DFNB48 does not overlap with the DFNA30locus.

The DFNB48 critical interval is located in a gene-richregion of chromosome 15 (UCSC Genome Bioinfor-matics, http://genome.ucsc.edu/). Interesting candidategenes present in this interval include a ligand-dependanttranscription factor referred to as retinal nuclear recep-tor subfamily 2 member 3 (NR2E3), Bardet-Biedl syn-drome locus (BBS4), and unconventional myosin(MYO9A). Myosins are motor proteins that hydrolyzeATP and translocate along actin filaments (Berg et al.2001). Mutations of myosins IA, IIA, IIC, IIIA, VI,VIIA, and XVA are associated with hearing loss in hu-mans (Friedman and Griffith 2003; Donaudy et al. 2003;Melchionda et al. 2001; Ahmed et al. 2003a; Gibsonet al. 1995; Weil et al. 1995; Liu et al. 1997a, 1997b;Probst et al. 1998; Wang et al. 1998; Lalwani et al. 2000;Liburd et al. 2001; Walsh et al. 2002; Donaudy et al.2004). The involvement of unconventional myosins inhereditary deafness is well documented (Resendes et al.2001; Ahmed et al. 2003b), and MYO9A transcripts arealso found in the inner ear of E16.5 mouse embryo(Gorman et al. 1999). Therefore, MYO9A is a goodcandidate for DFNB48.

NR2E3 is a member of the nuclear receptor subfamily2 (Kobayashi et al. 1999) and plays a key role in humanretinal photoreceptor differentiation and degeneration(Kobayashi et al. 1999). Mutations in NR2E3 causeenhanced S cone syndrome, a retinal disease (Haideret al. 2000). However, there is no evidence of a retinalphenotype in affected members of the five DFNB48families described here. BBS4 is clinically heterogeneousand characterized by retinitis pigmentosa, central obes-ity, polydactyly, orthopedic abnormalities, renal mal-formations, cognitive difficulties, and deafness withreduced penetrance (Mykytyn et al. 2001). The predictedprotein sequence of BBS4 shows strong homology to O-linked N-acetylglucosamine transferase (OGT; Mykytynet al. 2001). In humans, OGT has been implicated ininsulin resistance and may play a role in diabetes.However, there are no symptoms of diabetes or otherBBS4 symptoms in our DFNB48 family members.TMC3 is also located in the DFNB48 interval. This geneis a member of a family of eight channel-like paralogs(Kurima et al. 2003), and mutations of TMC1 areassociated with hereditary hearing loss in both humanDFNB7/B11 and DFNA36 and in dn and Bth mice(Kurima et al. 2002; Vreugde et al. 2002). Given thefunctional and structural diversity of ‘‘deafness genes’’and the variety of proteins that they encode, candidate

gene mutation analysis of DFNB48 will need to becomprehensive.

Acknowledgements We are grateful to the families for their partic-ipation in this study. We thank Dennis Drayna, Robert Morell,Julie Schultz, and Rehan S. Shaikh for their comments on thismanuscript. We also thank Sabiha Nazli and Farooq Sabar fortheir technical assistance. This study was supported by the HigherEducation Commission, Islamabad, Pakistan, and by the Interna-tional Centre for Genetic Engineering and Biotechnology, Trieste,Italy, under project CRP/PAK02-01 (contract no. 02/013). Thepart of this study conducted in the USA was supported by intra-mural funds from the National Institute on Deafness and OtherCommunication Disorders (ZO1 DC000035-07 and Z01DC000039-07).

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