Genetic Disorders of Adipose Tissue Development, Differentiation, and Death

ANRV285-GG07-08 ARI 12 August 2006 17:8

Genetic Disordersof Adipose TissueDevelopment,Differentiation, and DeathAnil K. Agarwal and Abhimanyu GargDivision of Nutrition and Metabolic Diseases, Department of Internal Medicine andthe Center for Human Nutrition, University of Texas Southwestern Medical Center atDallas, Dallas, Texas 75390-9052; email: [email protected]

Annu. Rev. Genomics Hum. Genet. 2006.7:175–99

First published online as a Review inAdvance on May 24, 2006

The Annual Review of Genomics and HumanGenetics is online atgenom.annualreviews.org

This article’s doi:10.1146/annurev.genom.7.080505.115715

Copyright c© 2006 by Annual Reviews.All rights reserved

1527-8204/06/0922-0175$20.00

Key Words

mandibuloacral dysplasia, acyltransferases, lamins, zincmetalloproteinase, PPAR gamma, AKT2

AbstractLack of adipose tissue, either complete or partial, is the hallmarkof disorders known as lipodystrophies. Patients with lipodystro-phies suffer from metabolic complications similar to those associ-ated with obesity, including insulin resistance, type 2 diabetes, hy-pertriglyceridemia, and hepatic steatosis. The loss of body fat ininherited lipodystrophies can be caused by defects in the develop-ment and/or differentiation of adipose tissue as a consequence ofmutations in a number of genes, including PPARG (encoding a nu-clear hormone receptor), AGPAT2 (encoding an enzyme involved inthe biosynthesis of triglyceride and phospholipids), AKT2 (encod-ing a protein involved in insulin signal transduction), and BSCL2(encoding seipin, whose role in the adipocyte biology remains un-clear). The loss of body fat can also be caused by the prematuredeath of adipocytes due to mutations in lamin A/C, nuclear laminaproteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of in-herited lipodystrophies as they relate to adipocyte biology and theirassociated phenotypic manifestations.

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CGL: congenitalgeneralizedlipodystrophy

INTRODUCTION

Several rare diseases manifest clinical fea-tures observed in many common conditions.Studying rare genetic diseases, thus, has im-plications for understanding pathogenesis ofcommon disease conditions and provides theopportunity to identify new biochemical path-ways that when defective result in disease.For example, identifying the molecular basisof familial lipodystrophies (disorders of adi-pose tissue development, differentiation anddeath) has provided new insights into sev-eral biochemical pathways in adipocyte biol-ogy (41). A major factor contributing to thedifficulties in identifying the genetic defectsresponsible for these disorders is the rela-tive rarity and lack of standardized definitionsand nomenclature for these disorders. Recentrapid advances in the capability to sequencegenes and careful phenotyping have resultedin the discoveries of the molecular basis ofmany of these disorders. For years, the studyof these rare disorders was negelected; de-spite, the fact that affected subjects developmany more common features associated withinsulin resistance, including hyperglycemia,hyperinsulinemia, hypertriglyceridemia, lowhigh-density lipoprotein (HDL) levels, hep-atic steatosis, hyperuricemia, acanthosis nigri-cans, hirsutism, polycystic ovarian syndrome,and coronary heart disease (44). Some formsof lipodystrophies are also characterized byan increased prevalence of hypertension (44).The severity of insulin resistance and otherassociated complications correlates with theextent of loss of adipose tissue.

Identification of the molecular basis oflipodystrophies has provided the promise ofadvancing our understanding of the biochem-ical defects in type 2 diabetes mellitus, hyper-lipidemia, and nonalcoholic hepatic steatosis.These advances have heightened the interestand increased the recognition of these syn-dromes. Pediatricians, endocrinologists, ge-neticists, reproductive endocrinologists, andgynecologists are increasingly diagnosing pa-tients with lipodystrophy.

Genetic lipodystrophies can be broadlyclassified into two main types of inheri-tance patterns: (a) autosomal recessive and (b)autosomal dominant. In some patients, thedisorder is sporadic and due to de novo muta-tions. For some syndromic disorders, the pre-cise pattern of inheritance remains to be char-acterized. A brief classification is provided inTable 1 and a detailed description of key clin-ical features is presented in Table 2.

AUTOSOMAL RECESSIVELIPODYSTROPHIES

Congenital GeneralizedLipodystrophy

Congenital generalized lipodystrophy(CGL), also known as Berardinelli-Seip syn-drome, is named after physicians Berardinellifrom Brazil and Seip from Norway, who pro-vided the original descriptions (16, 83) of thisdisorder. It becomes manifest in the perinatalperiod so pediatricians or neonatologiststypically diagnose the disorder. However,some cases are discovered later during life.Approximately 300 patients with this disorderhave been reported to date, with an estimatedworldwide prevalence of ∼1 in 10 million.Clusters of patients have been reported fromsome regions of Brazil and Lebanon, whereconsanguinity is more common.

Clinical features. Affected babies are bornwith a near complete absence of adipose tis-sue, which manifests as prominent muscles(Figure 1a). Affected children have increasedenergy intake supporting an increased rate ofgrowth. Bone age is typically advanced be-yond their chronological age and many pa-tients have enlarged hands, feet, and mandible(“acromegaloid” features). Umbilical herniasare frequently present in this disorder. Laterin childhood, patients develop severe acan-thosis nigricans affecting multiple areas of thebody.

Almost all subjects with CGL have hep-atomegaly (+/− splenomegaly) due to a fatty

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Table 1 Classification of genetic lipodystrophies

1. Autosomal recessivea. Congenital generalized lipodystrophy (CGL)b. Mandibuloacral dysplasia (MAD)c. SHORT syndromed. Neonatal progeroid syndrome

2. Autosomal dominanta. Familial partial lipodystrophyb. Pubertal-onset generalized lipodystrophyc. Hutchinson-Gilford Progeria syndrome–associated lipodystrophyd. SHORT syndrome

liver, which can result in cirrhosis. Irregularmenstruation, oligo-amenorrhea, hirsutism,clitoral enlargement, and polycystic ovariesare frequent in affected women. Only a fewaffected women have had successful pregnan-cies. Some patients develop multiple focallytic lesions in the long bones of the body afterpuberty (37), most likely due to an inability toreplace hematopoeitic marrow with adiposetissue. Some patients also have cardiomyopa-thy and mild mental retardation (10, 84, 98).

Extreme insulin resistance is a majorcharacteristic of this disease and is asso-ciated with severe hypoleptinemia and hy-poadiponectinemia (55). Most patients haveelevated fasting and postprandial plasma lev-els of insulin. Although most patients donot develop diabetes mellitus until puberty,some neonates develop hyperglycemia, whichrequires high doses of insulin to control.Severe hypertriglyceridemia can predisposepatients to recurrent episodes of acute pan-creatitis. Plasma levels of low-density lipopro-tein (LDL) cholesterol are typically normalor reduced, and plasma levels of high-densitylipoprotein (HDL) cholesterol are often low.It is not clear if these patients are prone todevelop atherosclerotic vascular disease

Molecular basis. Positional cloning strate-gies using the conventional genome-widelinkage analysis identified two loci for CGL.We identified one locus on human chromo-some 9q34 (48) and Magre et al. (66) dis-

AGPAT2:1-acylglycerol-3-phosphate-O-acyltransferase 2gene

BSCL2:Berardinelli-SeipCongenitalLipodystrophy 2gene

covered the second locus on chromosome11q13. The defective gene on chromosome 9was 1-acylglycerol-3-phosphate-O-acyltran-sferase 2 (AGPAT2). Several mutations in-cluding nonsense, frameshift, deletion, andmissense mutations in AGPAT2 have nowbeen reported in affected patients (2,3).AGPATs are members of the acyltransferasefamily of enzymes with eight known iso-forms, each of which is encoded by a differentgene (4, 62, 63, 103). AGPATs play a criti-cal role in the biosynthesis of glycerophos-pholipids and triacylglycerols. The enzymecatalyzes the conversion of lysophosphatidicacid (1-acylglycerol-3-phosphate) to phos-phatidic acid (1,2 diacylglycerol-3-phosphate)by adding a fatty acyl group at the sn-2 po-sition (Figure 2) (62, 100). AGPAT2 is pre-dominantly expressed in the omental adiposetissue (2, 32, 33, 100); it is likely that re-duced levels or absence of AGPAT2 activ-ity causes lipodystrophy either by impairingtriglyceride synthesis in adipocytes or by af-fecting adipocyte differentiation and functionby interfering with the biosynthesis of phos-pholipids.

The defective gene on chromosome 11q13that causes CGL is the Berardinelli-Seip Con-genital Lipodystrophy 2 (BSCL2) gene, whichwas predicted to encode a 398–amino acidprotein called seipin (66). Based on sequencesimilarities among different species, seipin has64 additional residues at the amino termi-nus that were not included in the original

www.annualreviews.org • Genetic Disorders of Adipose 177

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Tab

le2

Clin

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feat

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mild

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lack

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Neo

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Figure 1Patients with congenital generalized lipodystrophy (a) and familial partiallipodystrophy (b). Panel a shows a 34-year-old female of Hispanic originwith congenital generalized lipodystrophy (type 1) due to mutations inthe AGPAT2; there is a generalized lack of body fat with sparing of thepalms and soles and extreme muscularity. She developed diabetes mellitusat the age of 26 and developed acanthosis nigricans in the neck region andaxillae as well as acromegaloid features. Panel b shows a 19-year-old whitewoman with familial partial lipodystrophy, Dunnigan variety, due to aheterozygous missense mutation in the LMNA gene. She lost fat from theextremities and trunk at puberty and had excess fat accumulation in theface and neck region.

description of the gene (8); however, nodisease-causing mutation has been detected inthis predicted region. BSCL2 mRNA is highlyexpressed in the brain and testis, but expres-sion levels in adipose tissue are low (3, 66). Al-though it has been suggested that mutations in

seipin result in a defect in the hypothalamo-pituitary axis, the precise mechanism of de-velopment of lipodystrophy in patients withBSCL2 mutations remains unclear (66).

Parents and siblings of subjects with thisform of lipodystrophy, who are heterozy-gous for disease-causing mutations in BSCL2,do not have any detectable phenotype. In-terestingly, mutations of the N-glycosylation(N-X-S/T) motif of BSCL2 were recentlyidentified in subjects with an autosomal dom-inant distal hereditary motor neuropathy andSilver syndrome (102). Thus, mutations inseipin are associated with both mild mentalretardation in CGL, type 2, and distal hered-itary motor neuropathy and Silver syndrome,indicating the important role seipin plays inboth the central and peripheral nervous sys-tem. The homology of seipin to midasin, anAAA (ATPases Associated to a variety of cellu-lar Activities) domain containing nuclear pro-tein involved in RNA transport, might yieldsome clues as to how mutant forms of seipincause two clinically distinct syndromes (8).

CGL patients with BSCL2 mutations havea more severe loss of adipose tissue that affectsboth the mechanical and metabolically activeadipose tissue depots than is seen in subjectswith AGPAT2 mutations where the fat lossis restricted to metabolically active adiposetissue (Figure 3). BSCL2 may contribute tothe early development of preadipocytes frommesenchymal cells.

Genetic and phenotypic heterogeneity.CGL patients with AGPAT2 (CGL, type 1)and BSCL2 mutations (CGL, type 2) havedistinct phenotypic features (2, 10, 90, 98).Focal lytic lesions in the appendicular skele-ton are more prevalent in CGL, type 1 (90),whereas patients with CGL, type 2 can de-velop cardiomyopathy and mild intellectualimpairment (2, 10, 98) not seen in CGL, type1. Both forms of CGL are associated with nearcomplete loss of metabolically active adiposetissue in most subcutaneous, intraabdomi-nal, intrathoracic, and bone marrow fat de-pots, as ascertained by whole-body magnetic

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Glycerol-3-phosphate

Fatty acid-CoA

Lysophosphatidic acid

Phosphatidic acid

Pi

Diacylglycerol

Triacylglycerol

2-monoacylglycerol

AGPATs

GPATs

PAPs

DGATs

MGATs

AGPAT2

CoA

Phosphatidyl inositolCardiolipin

Phosphatidyl cholinePhosphatidyl ethanolaminePhosphatidyl serine

DGK

Fatty acid-CoA

CoA

Fatty acid-CoA

CoA

Fatty acid-CoA

CoA

Figure 2Pathways for the biosynthesis of triacylglycerol. Glycerol-3-phosphate undergoes acylation at the sn-1position by glycerol-3-phosphate acyltransferase (GPAT), to form 1-acylglycerol-3-phosphate orlysophosphatidic acid (LPA). LPA is then acylated at the sn-2 position by 1-acylglycerol-3-phosphateacyltransferase (AGPAT) to form phosphatidic acid (PA). In the next step, the phosphate group isremoved by phosphatidate phosphohydrolase (PAP) to produce diacylglycerol (DAG). DAG is thenacylated at the sn-3 position by diacylglycerol acyltransferase (DGAT) to produce triacylglycerol (TG).DAG kinase (DGK) can phosphorylate DAG to synthesize PA. TG can also be synthesized via theacylation of 2-monoacylglycerol by the enzyme monoacylglycerol-acyltransferase (MGAT), which isexpressed at high levels in the small intestine. PA and DAG are also substrates for the synthesis ofglycerophospholipids. PA is the substrate for synthesis of phosphatidylinositol and cardiolipin.Phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine are synthesized from DAG.LPA and related lipid molecules are also involved in signal transduction and are ligands for Gprotein-coupled receptors. Figure 2 is reproduced from Reference 7. Copyright 2003, with permissionfrom Elsevier.

resonance imaging (90). Patients with CGL,type 1 have preserved mechanical adipose tis-sue depots in the palms, soles, scalp, retro-orbital, and peri-articular regions, whereas inCGL, type 2 there is no fat sparing in theseregions (Figure 4) (24, 43, 90). As expecteddue to the more complete lipodystrophy inCGL, type 2, these patients have lower levelsof serum leptin (10).

Most patients with CGL are either ho-mozygous or compound heterozygotes formutations in AGPAT2 or BSCL2. However,occasionally only a single mutation in oneof these genes has been identifed. The dis-ease is not linked to either locus in a few

pedigrees of patients with CGL, suggestingas yet unidentified loci for CGL (10). Otherlipodystrophic disorders, such as acquiredgeneralized lipodystrophy, leprechaunism,childhood-onset generalized lipodystrophydue to rare LMNA mutations, and neona-tal progeroid syndrome, can present as phe-nocopies of CGL, so must be excluded. Itremains possible that CGL, type 3 patientsmay harbor heterozygous mutations in twoacyltransferases catalyzing different steps oftriglyceride biosynthetic pathway. For ex-ample, a patient may develop generalizedlipodystrophy due to being heterozygous formutations in both AGPAT2 and another gene


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AGPAT,

Myocytes Osteoblasts

stem cells

Fasting Feeding

C/EBPβC/EBPδ

C/EBP

PPARγ /RXRα

BSCL2?

Transcriptionfactors?

Adipogenic factors(insulin, cortisol, etc.)

SREBP1cLipogenesis(FAS, ACC,

GPAT, DGAT)

Apoptosis

aitnereffiDtnempoleveD sisotpopa/htaeDnoit

Mesenchymal Pre-adipocyte Adipocyte Cell deathMature adipocyte

Figure 3Pathways involved in the development, differentiation, and death of adipocytes. The pluripotentmesenchymal stem cells respond to yet-to-be fully characterized cues to commit to formingpreadipocytes. Preadipocytes respond to hormonal signals (insulin and steroids) to initiate changes inlevels of expression of selected transcription factors leading to the differentiation to mature adipocytes.In vitro and in vivo models have established that C/EBPβ/δ are the initial genes upregulated in responseto hormones, etc. These transcription factors stimulate other transcription factors such as PPARγ,C/EBPα, and SREBP1c. Other genes that are downregulated in this process include cellular factors likePREF1, an adipogenesis inhibitor. Lipogenic genes, such as FAS, ACC, GPAT, AGPAT, and DGAT, areupregulated, resulting in increased biosynthesis of triglycerides and phospholipids. Lipid droplet size isreduced upon fasting and increases with increased substrate availability. BSCL2 (seipin) is likely involvedin adipocyte development and early differentiation, whereas the AGPAT2 gene more likely affectstriglyceride synthesis but may also contribute to adipocyte differentiation. Clinical evidence fromlipodystrophy patients harboring LMNA or ZMPSTE24 mutations suggests that nuclear dysfunction mayaccelerate apoptosis/death of mature adipocytes.

involved in triglyceride biosynthesis, such asother AGPATs, DGATs, or GPATs. Examplesof such digenic inheritance resulting in com-plex phenotypes have been described for othermetabolic disorders such as cortisone reduc-tase deficiency (30) and severe insulin resis-tance (81).

Genotype and phenotype variation. Al-though the functional defects in the enzy-matic activities of many of the AGPAT2 mu-tations have been characterized in vitro (53)(Figure 5), there appears to be no correla-tion between the genotype and phenotype.All missense mutations characterized to datehave some residual functional activity (>20%of the wild type). Only one homozygous mis-sense mutation, E172K (affecting one of theconserved motifs, EGTR, which most likelyparticipates in fatty acid binding), has been

identified in AGPAT2 in CGL, type 1 patients(4, 66a). All other individuals with a missensemutation in one allele have a null mutation inthe other allele. Subjects who are homozygous(or compound heterozygous) for other mis-sense mutations of AGPAT2 may have a moresubtle phenotype that could range from beinglean and resistant to diet-induced obesity tohaving mild generalized lipodystrophy and in-sulin resistance. Individuals heterozygous fornull mutations, predicted to have ∼50% of thewild-type AGPAT2 activity, have no obviousphenotype. These individuals may have moresubtle metabolic perturbations, such as hy-pertriglyceridemia, low plasma levels of HDLcholesterol, or impaired glucose tolerance.

Most of the BSCL2 mutations reportedin patients with CGL have been null muta-tions due to deletions, insertions, frameshifts,or premature terminations. A single missense

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mutation (A212P) has been identified (66, 98).Individuals homozygous for the A212P muta-tion (two women and three men) are clinicallyindistinguishable from subjects homozygousfor null mutations in BSCL2. The five subjectshomozygous for the A212P mutation had on-set of lipodystrophy at birth, mild to moder-ate intellectual impairment, and hypertrophiccardiomyopathy, three died prematurely be-tween 24–35 years of age (98).

Mandibuloacral Dysplasia–AssociatedLipodystrophy

Mandibuloacral dysplasia (MAD) is extremelyrare and has been reported in only ∼40 pa-tients. Based on genotyping and phenotyping,there appears to be more than two types ofMAD. Most of the initial patients describedwere from consanguineous pedigrees fromItaly; however, patients of other ethnicitieshave also been reported.

Clinical features. This disorder presentswith mandibuloacral dysplasia (71, 89), whichis characterized by mandibular hypoplasiaand resorption of the clavicles and termi-nal phalanges (acro-osteolysis). Some patientspresent with progeroid features and have abird-like facies with a beaked nose. These pa-tients characteristically have a high-pitchedvoice, and ectodermal defects, such as skinatrophy, alopecia, and nail dysplasia. Otherclinical features include delayed closure ofcranial sutures, joint contractures, mottledcutaneous pigmentation, and short stature.Patients occasionally present with hypogo-nadism and sensorineural deafness. These pa-tients also have an associated lipodystrophy,which presents in two patterns: partial loss ofsubcutaneous fat from the extremities but nor-mal or excess fat in the face, neck, and truncalregions similar to that seen in patients withautosomal dominant, familial partial lipodys-trophy of the Dunnigan variety (FPLD)(type A), and more generalized loss of sub-cutaneous fat in the face, trunk, and extrem-ities (type B) (89). Along with lipodystrophy,

Figure 4Axial magnetic resonance T1-weighted images through the orbits andsagittal magnetic resonance images through the orbits and foot in a patientwith CGL, type 1, (a, d, g) CGL, type 2 (b, e, h), and a normal subject(c, f, i ). Body fat appears as regions of increased signal intensity. The CGL,type 1 patient has normal amounts of fat in the retro-orbital region,temporal region, and subcutaneous area of the scalp, and plantar region, butlack subcutaneous fat in the submental, anterior, and posterior neck regions.The CGL, type 2 patient had a near total lack of retro-orbital and plantarfat as well as subcutaneous fat from the temporal region, scalp, and neck.Normal fat distribution in the retro-orbital, temporal, scalp, submental,cervical, and plantar regions is shown in the images of the normal subject.Reprinted from Reference 90. Copyright 2005, The Endocrine Society.

MAD:mandibuloacraldysplasia

FPL: familial partiallipodystrophy

some patients also develop hyperinsulinemia,insulin resistance, impaired glucose tolerance,diabetes mellitus, and hyperlipidemia (84).

Molecular basis. The pattern of lipodystro-phy among patients with MAD and FPLDwas reported to be similar (89), suggest-ing that these two disorders may be dueto defects in the same gene. Novelli et al.(71) identified 5 Italian offsprings of consan-guineous matings with MAD (type A) whowere homozygous for a missense mutation(R527H) in the LMNA gene. Additional ho-mozygous (A529V and K542N) or compound


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Median enzymatic activity

(% of wild type)

0

10

20

30

40

50

60

70

80

90

100

A239V

G136R

L228P

140delF

221delGT 252delMRT

R68X V167fsX183

D180fsX251

Figure 5In vitro enzymatic activity of AGPAT2 mutants. The enzymatic activity of various mutants of AGPAT2was determined by expressing the recombinant protein in Chinese hamster ovary (CHO) cells andmonitoring the conversion of 3H-lysophosphatidic acid (LPA) to 3H-phosphatidic acid (PA). The medianvalues are plotted as percentages of the wild-type activity (53). The missense mutants are shown inyellow, deletion mutants in blue, and null mutants in purple.

heterozygous (R472C/R527C) LMNA muta-tions in other patients with MAD have beendescribed by us and others (22, 42, 78). Allof these mutations cluster in the C-terminalregion of LMNA. Subjects heterozygous forthese mutations reveal no evidence of skeletalabnormalities or lipodystrophy.

The LMNA gene is located on chro-mosome 1q21-22 and contains 12 exons.Through alternative splicing in exon 10, theLMNA gene encodes for two major isoforms,lamin A and C (64). Lamin A is produced bypost-translational modification of its precur-sor prelamin A (91). Prelamin A is encoded byall 12 exons of LMNA and contains a CAAXmotif at the C terminal. Post-translationalmodification of prelamin A occurs in astep-wise process including (a) farnesyla-tion, (b) proteolytic cleavage of the terminalthree amino acids (AAX), (c) carboxymethy-lation of cysteine residue, and (d) anotherproteolytic cleavage of 15 carboxy-terminal

amino acids, resulting in formation of maturelamin A. The enzyme, zinc metalloproteinase(ZMPSTE24), is responsible for the first andsecond step of the proteolysis. Both maturelamin A and lamin C share the N-terminal566 amino acids, but lamin A has 98 uniquecarboxy-terminal amino acids and lamin C has6 unique C-terminal amino acids.

Lamins form hetero- or homo-dimericcoiled-coil structures intercalated betweenchromatin and the inner nuclear membrane(20, 36). Besides lamins A and C, laminsB1 and B2, which are products of two dif-ferent genes, also participate in the forma-tion of nuclear lamina. Mutations in lamins Aand C cause many other syndromes includingcardiomyopathy, muscular dystrophies, neu-ropathy, and progeria (18, 25, 27, 34, 70).The precise mechanisms by which defectivelamins A and C cause these various syndromesremain unclear. It is hypothesized thatdefective interactions of lamins A and C with

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chromatin or other nuclear lamina proteinsduring cell division leads to apoptosis and pre-mature cell death. Consistent with this hy-pothesis, skin fibroblasts from patients withvarious types of laminopathies show abnormalnuclear morphology including nuclear blebsand multilobulated nuclei (Figure 6). How-ever, why specific LMNA mutations cause pre-dominantly skeletal and cutaneous dystrophybut less severe lipodystrophy in patients withMAD remain unclear.

Various mouse models have been devel-oped to better understand the pathogenesisof syndromes due to LMNA mutations. TheLmna null mice, though not embryonic lethal,show severe growth retardation and die pre-maturely at 5–6 weeks of age due to muscu-lar dystrophy and cardiomyopathy (95). Theyhave little adipose tissue but are not insulinresistant, presumably due to insufficient timeto develop the metabolic disorder (26).

In addition, three knock-in mouse mod-els for Lmna have been created, althoughnone of them are specific for either MADor FPLD (13, 68, 69). The first one withL530P mutation was intended to recreate fea-tures of autosomal dominant Emery-Dreifussmuscular dystrophy (68). The heterozygousLmnaL530P/+ mouse did not show any phe-notype, but the homozygous LmnaL530P/L530P

mouse replicated features of human progeria(68). These mice died by 4 weeks of age andhad bone, muscle, and skin pathology. Thedefect did not appear to be due to defectsin adipocyte differentiation since myoblastsand fibroblasts from the LmnaL530P/L530P micewere capable of differentiation into adipocytesin vitro (68). This suggests that structural cel-lular defects may cause cell death by a combi-nation of altered transcription, and mislocal-ization of nuclear proteins.

Another murine model was developed torecreate Emery-Dreifuss muscular dystro-phy by inserting a H222P substitution intoLMNA(13). The heterozygous LmnaLH222P/+

mice were indistinguishable from wild-typemice but the homozygous LmnaH222P/H222P

mice developed muscle degeneration, dislo-

Figure 6Nuclear morphology of skin fibroblasts in patients with LMNA mutations.(a) Indirect immunofluorescence microscopy using lamin A/C antibody inskin fibroblasts obtained from a control subject shows normal nuclearmorphology. (b) Nuclear bleb in one of the nuclei in a patient withmandibuloacral dysplasia with homozygous A529V LMNA mutation.(c) Multilobulated nuclei were seen in a patient with R133L heterozygousLMNA mutation who had generalized lipodystrophy, diabetes, and atypicalprogeroid syndrome. (d ) Occasional nuclear blebs were observed in apatient with R133L heterozygous LMNA mutation who presented withmild peripheral lipodystrophy and atypical progeroid syndrome. Reprintedwith permission from References 42, 59. Copyright 2005, The EndocrineSociety.

cation of heterochromatin, and activation of atranscription factor, Smad, in both the heartand skeletal muscle. The LmnaN195K/N195K

mouse generated to replicate the cardiomy-opathy (69) showed all the features of the dis-ease. The transcription factor Hf1b/sp4 andthe gap junction protein connexin 40 and 43were both misexpressed or mislocalized in thecardiomyocytes of these mice.

We identified a second locus that wasdefective in a patient with MAD (5). Thisseverely affected patient from Belgium,who had progeroid features and general-ized lipodystrophy, had compound heterozy-gous mutations (F361fsX379 and W340R)in ZMPSTE24 (5). This young woman died


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ZMPSTE24: zincmetalloproteinasegene

at age 27 due to complications of chronicrenal failure resulting from focal segmentalglomerulosclerosis (5). Subsequently, another2-year and 9-month-old girl who died prema-turely with MAD, sclerodermatous skin, andprogeroid features was reported to have com-pound heterozygous ZMPSTE24 mutations(F361fsX379 and N265S) (87). Recently, a 5-year-old Turkish boy with overlapping fea-tures of MAD and progeria was reported tohave a heterozygous R654X LMNA mutationand a homozygous V402SfsX403 ZMPSTE24mutation (28). Another patient of Europeanorigin with MAD, who required renal trans-plantation due to focal segmental glomeru-losclerosis, was reported to have compoundheterozygous F361fsX379 and N265S muta-tions (11). Because ZMPSTE24 is critical forthe post-translational proteolytic processingof prelamin A to mature lamin A, it is likelythat accumulation of farnesylated prelamin Aor lack of mature lamin A is responsible forthe phenotypic effects of these mutations (91).The embryonic fibroblasts obtained fromZMPSTE24 null mice show accumulation ofprelamin A (17, 75). In addition, these miceshow retarded growth and premature death,lipodystrophy, progeria, and skeletal defectsincluding multiple spontaneous bone frac-tures (17, 75). Recent studies show improve-ment in phenotype of Zmpste24−/− mice withfarnesyl transferase inhibitor therapy suggest-ing primary role of accumulation of farne-sylated prelamin A in causing the pathology(38, 104).

Genetic and phenotypic heterogeneity.Patients with ZMPSTE24 mutations appear tohave a more severe phenotype than MAD pa-tients with LMNA mutations (71, 88) includ-ing early onset of skeletal defects such as acro-osteolysis, more progeroid appearance, anddevelopment of subcutaneous calcified nod-ules on the phalanges. In addition, progres-sive glomerulopathy has not been observed inMAD patients with LMNA mutations (5).

Some patients with MAD have mandibu-lar hypoplasia along with other clinical fea-

tures but do not develop clavicular resorp-tion or acro-osteolysis. These patients alsodo not harbor LMNA or ZMPSTE24 vari-ants, suggesting the possibility that there areother genes that are defective in MAD (5).Patients with MAD need to be differentiatedfrom those with Hutchinson-Gilford Proge-ria, atypical progeroid, Hajdu-Cheney, con-genital insensitivity to pain with anhidro-sis, Haim-Munk, and Papillon-Lefevre syn-dromes because of some overlapping features.

Genotype and phenotype variation. MADpatients who are homozygous for the K542NLMNA mutation have severe progeroid fea-tures, including alopecia, lack of eyebrowsand eyelashes, early-onset (age 1–2) acro-osteolysis, and absent or impaired sexual mat-uration. Two of these patients died at age10 and 16 (78). A Turkish girl who was ho-mozygous for an A529V missense mutationin LMNA lacked breast development despitehaving normal menarche and menses (42).These findings are in contrast to patientswith the homozygous R527H LMNA mu-tation who usually live beyond the age of30 and have normal breast development andsexual maturation (71, 89). Other subtle phe-notypic differences in MAD patients withdifferent LMNA mutations remain to be char-acterized. These phenotypic differences in pa-tients with mutations of different residues arelikely attributable to the differences in the ter-tiary structures of lamins A and C.

SHORT Syndrome–AssociatedLipodystrophy

Approximately 30 patients have been re-ported to have SHORT syndrome, anacronym for features such as short stature,hyperextensibility of joints and/or inguinalhernia, ocular depression, Rieger anomaly andteething delay (52, 85, 93). Rieger anomaly in-cludes eye abnormalities such as hypoplasia ofiris stroma, prominent Schwalbe ring, irido-corneal synechiae, micro- or megalo-cornea,

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and teeth abnormalities such as hypodontia,microdontia, enamel hypoplasia, and atypicalteeth. Lipodystrophy in these patients com-monly affects the face, upper extremities, andsometimes the trunk. Both autosomal reces-sive (52, 85) and autosomal dominant pat-terns of inheritance have been reported (1, 14,93). Some investigators have reported a differ-ent pattern of lipodystrophy in patients withan autosomal dominant variety affecting onlythe face, gluteal region, and elbows (1, 14),but others found similar loss of fat as seen inthe autosomal recessive variety (93). Some pa-tients develop diabetes in the second and thirddecade. The precise molecular basis of thesedisorders remains unclear.

Neonatal Progeroid Syndrome(Wiedemann-RautenstrauchSyndrome)-AssociatedLipodystrophy

This syndrome has been reported in about 30patients (77, 79, 101) and is characterized bya progeroid appearance consisting of a trian-gular, aged-looking face with a relatively largeskull, prominent subcutaneous veins, particu-larly in the scalp, sparse scalp hair, large ante-rior fontanelle, and generalized lipodystrophyat birth. Accumulation of subcutaneous fat oc-curs in the sacral and gluteal areas (60, 77).About 50% of the patients die before the ageof 6 (77). The genetic basis of this syndromeremains unknown.

AUTOSOMAL DOMINANTLIPODYSTROPHIES

Familial Partial Lipodystrophy,Dunnigan Type

FPLD is named after Dunnigan, who alongwith his colleagues provided a detailed de-scription of the syndrome (31). So far, approx-imately 300 men and women mostly of Euro-pean origin have been reported to have FPLD(40, 54).

Clinical features. Affected children do notshow any abnormalities in body fat distri-bution.The lipodystrophy manifests at thetime of puberty with a gradual loss of adi-pose tissue from the extremities and trunk(Figure 1b). With increasing age, the loss offat continues from other regions of the body,particularly the anterior truncal region (45).Some regions such as the face, chin, neck, andintra-abdominal region are spared. Excess fataccumulates in the spared areas, resulting in a“double chin” and a Cushingoid appearance.There is also preservation of intermuscularand bone marrow fat (45). It is easier to rec-ognize FPLD in women than men, due to theincrease in muscle definition in the extremi-ties. About 20–33% of patients have acantho-sis nigricans, hirsutism, menstrual abnormal-ities, and polycystic ovaries (40).

Metabolic complications such as diabetes,hyperlipidemia and atherosclerotic vasculardisease also occur more often in affectedwomen than men (40, 56). In our experience(40), women have twice the prevalence of di-abetes and more than a three-times-higherprevalence of atherosclerotic vascular diseasethan men with this disorder. Women also hadsignificantly higher plasma levels of triglyc-erides and significantly lower high-densitylipoprotein cholesterol concentrations thanmen (40). Several explanation may exist forthe predisposition of women with FPLD todevelop complications of insulin resistance.First, women have increased peripheral sub-cutaneous fat deposition compared with men,consequently women with FPLD are subjectto more fat loss than men. Second, pregnancyis a time of efficient fat storage and as womenwith FPLD may not be able to accumulate fatin most subcutaneous regions, they may accu-mulate fat in the intra-abdominal region, pre-disposing them to metabolic complications.Consistent with these, among women withFPLD, the risk factors for diabetes includedmultiparity and excess fat deposition in thenonlipodystrophic regions such as the chin(54). Some patients develop cardiac problems


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PPARG: peroxisomeproliferator-activatedreceptor-γ gene

and occasionally patients develop myopathy(46).

Molecular basis. We mapped the gene caus-ing FPLD to chromosome 1q21-22 (76) andthen Cao and Hegele (21) identified a mis-sense (R482Q) mutation in the LMNA gene ina Canadian pedigree. Since then, several mis-sense mutations in the LMNA gene have beenreported in patients with FPLD (46, 54, 86,94, 99). It is still unclear how these LMNA mu-tations promote lipodystrophy and why theadipose tissue in the face, neck, and intra-abdominal regions is spared.

Genotype and phenotype variation. Ap-proximately three fourths of FPLD patientsharbor missense mutations involving the argi-nine residue at position 482 (R482Q, R482W,or R482L) (54). Other mutations in the globu-lar C-terminal (tail) portion of the protein en-coded by exons 8–11 have also been described(21, 54, 86, 94, 99). We reported a milder formof FPLD in patients with the R582H muta-tion in exon 11, which affects lamin A andnot lamin C (47). Some patients with R28Wand R62G mutations in exon 1 have an as-sociated cardiomyopathy, which presents aspremature congestive heart failure or with ar-rhythmias, such as atrial fibrillation and con-duction system disturbances, requiring pace-maker implantation (46). A few patients alsohave a mild proximal myopathy (46, 99). Thus,LMNA mutations cause a multisystem dystro-phy syndrome affecting adipose tissue, car-diac, skeletal muscle, nerve, cutaneous, andskeletal tissue (46). However, why some mu-tations cause more pathology in skeletal mus-cles and others in nerve, cutaneous, or skeletaltissue remains unclear.

Familial Partial Lipodystrophy Dueto Peroxisome Proliferator-ActivatedReceptor-γ Mutation

Following our initial report of a heterozygousmissense mutation, R397C, in the PPARγ

gene in a 64-year-old woman of European

descent with partial lipodystrophy, diabetes,hypertriglyceridemia, hypertension, and hir-sutism (6), nine other subjects (five fe-males and four males) have been reportedto have FPL due to PPARG missense muta-tions (V290M, F360L, P467L, and PPARG4promoter-14A>G) (12, 57, 82). These pa-tients have variable manifestations of insulinresistance such as diabetes, hypertension, andhypertriglyceridemia. The onset of lipodys-trophy seems to vary from puberty to mid-adulthood. All patients have fat loss from theextremities; however, facial fat loss has beenvariable (6, 57, 82). It appears that lipodys-trophy mainly affects the distal regions of theextremities such as the forearms and calvesmore than the proximal regions (6).

Given the essential role that PPARγ playsin adipocyte differentiation (80), and the highlevel of expression of this gene in the adi-pose tissue, it is likely that PPARG missensemutations are dominant negative mutationscausing lipodystrophy by reducing adipo-genesis. Because the affected patients donot develop lipodystrophy during childhood,it appears that PPARγ-mediated adipocytedifferentiation continues during adulthood.

The homozygous deletion of Pparg in miceis embryonic lethal (15, 61). However, the het-erozygous mice have reduced adipose tissueand develop insulin resistance (61, 67). In ad-dition, tissue-specific knockout mice for Pparghave also been generated such that the geneis inactivated only in the liver, muscle, or adi-pose tissue. All of these tissue-specific knock-outs are insulin resistant (97), but it was notreported whether the mice have lipodystro-phy. Recently, the missense mutation P465Lwas introduced into the mouse Pparg gene(96). The heterozygous mice (PpargP465L/+)have selective loss of adipose tissue from theretroperitoneal and gonadal fat depots, withsparing of inguinal fat. The PpargP465L/+ miceare insulin resistant and develop hyperten-sion. Although there is a consensus for thecritical role of PPARγ in adipocyte differen-tiation, the depot-specific sparing of adiposetissue remains unclear. It is likely that there

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are other nuclear receptors besides PPARγ

that may play a role in differentiation in otheradipose tissue depots.

Familial Partial Lipodystrophy Dueto the v-AKT Murine ThymomaOncogene Homolog 2Gene Mutation

Recently, George et al. (50) reported a het-erozygous missense mutation, R274H, in thev-AKT murine thymoma oncogene homolog2(AKT2) gene in a family in which affectedsubjects developed insulin resistance, diabetesmellitus, and hypertension. The proband, a34-year-old female, had partial lipodystro-phy affecting her extremities (Figure 7)(S. O’Rahilly, personal communica-tion). AKT2 belongs to the familyof phosphoinositide-dependent serine/threonine kinases, also known as proteinkinase B (PKB). AKT2 is predominantlyexpressed in insulin-sensitive tissues and isinvolved in postreceptor insulin signaling(Figure 8). In mammals, there are threeknown isoforms, AKT-1, 2, and 3, eachencoded by a different gene, which sharesignificant homology among themselves (92).These kinases also have very similar sub-strates but display tissue-specific expressionand function. Akt2−/− mice display featuresof insulin resistance and develop diabetes(49). These mice have reduced adiposetissue mass in the inguinal, subcutaneousand epididymal/gonadal depots with mildhepatomegaly. It is possible that reducedadipocyte differentiation, as seen in 3T3-L1cells expressing the mutant form of AKT2, ordysfunctional postreceptor insulin signaling,may be responsible for the developmentof lipodystrophy in patients with AKT2mutations.

Other Types of FamilialPartial Lipodystrophy

No molecular defect in the LMNA, PPARG,or AKT2 genes has been identified in a subset

Figure 7Lipodystrophy of the lower extremities in a patientheterozygous for a missense mutations in AKT2(R274H) AKT2. Panel a shows the posterior viewof the left hip, indicating marked loss ofsubcutaneous fat with prominent muscularity ofthe gluteal muscle and skin creases. Panel b showsthe posterior view of the lower extremities withincreased muscular definition due to loss ofsubcutaneous fat from the thighs and calves.Photographs courtesy of Stephen O’Rahilly.

AKT2: v-AKTmurine thymomaoncogene homolog 2gene

of FPL patients, suggesting that there are yet-to-be-determined additional genes that aredefective in FPL (A. Agarwal & A. Garg, per-sonal observation; 58). These patients seemto have a different pattern of fat loss thanthose with FPLD, but the distinctive pheno-typic differences between these patients andthose with FPL due to PPARG or AKT2 mu-tations remain to be identified (Figure 9).FPL patients should be carefully distin-guished from those with Cushing’s syndrome,truncal obesity, multiple symmetric lipomato-sis due to alcohol intake, and acquired gener-alized lipodystrophy.

Pubertal-OnsetGeneralized Lipodystrophy

Two unrelated patients of European originwho are heterozygous for a missense muta-tion in LMNA (R133L) have been describedwith this type of lipodystrophy (23, 59). Bothpatients had a normal fat distribution at birthbut developed generalized lipodystrophy,


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PIP2P P

P P

P P

PIP3

P110

GSK3β

Active AKT2(PKB)

FKHR

(Cell survival mode)Transcriptional activation

(glucose metabolism)

P85

Insulin receptor

Insulin

PH

Figure 8Role of AKT2 in intracellular insulin receptor signaling pathway. Insulin binding to the insulin receptoractivates phosphoinositol-3-kinase (PI3K), which phosphorylates membrane-bound phosphatidylinositol 4,5 phosphate (PIP2) to phosphatidyl inositol 3,4,5 phosphate (PIP3). AKT2, by virtue of itspleckstrin homology (PH) domain, is then recruited to the membrane, where it is phosphorylated by thephosphatidyl inositol-dependent kinase 1 (PDK1). The active form of AKT2 upregulates genes involvedin glucose metabolism and downregulates proteins like glycogen synthase kinase 3 β(GSK3β) andforkhead/FoxO transcription factor (FKHR).

diabetes, and hypertriglyceridemia after pu-berty. The patients have atypical progeroidfeatures, such as early graying of the hairwith thinning of eyebrows, beaked nose, andatrophic skin over the hands and feet. Skinfibroblasts from one of these patients hada markedly abnormal nuclear morphology(Figure 6b). However, another patient witha similar R133L heterozygous mutation ofLMNA of African-American origin had onlymild lipodystrophy involving only the distalextremities; skin fibroblasts from this patientdid not display a major alteration in nuclearmorphology (Figure 6d ). The reason for thedifference in phenotype in this subject, whencompared with the others identified withthis same mutation remains unclear. Varia-

tions in phenotypic expression in this disor-der may be due to differences in genetic back-ground, in methylation and imprinting, orin intra-uterine and post-natal environmentalfactors.

Other Rare Varieties

An autosomal dominant generalized lipodys-trophy with acromegaloid features and onsetafter 18 years of age was reported in a pedigreefrom Brazil (74). In another pedigree, lipodys-trophy of the lower extremities was observedin two siblings with unbalanced transloca-tion involving chromosome 8p and 10p. Re-cent data from Hutchinson-Gilford proge-ria syndrome patients with heterozygous

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Figure 9Axial T1-weighted magnetic resonance images through the thigh and calf in patients with familial partiallipodystrophy, Dunnigan (FPLD) variety due to a heterozygous LMNA mutation; a subject with FPL dueto a heterozygous PPARG mutation; a subject with another type of FPL; and a normal subject. Body fatappears as increased signal intensity. The FPLD patient has a near complete loss of subcutaneous fat, butfat in the intermuscular fasciae and bone marrow is preserved. The patient with FPL due to a PPARGmutation has decreased amounts of subcutaneous fat particularly in the antero-lateral and posterior thighand calf region, and the patient with another type of FPL (not due to LMNA, PPARG, and AKT2mutations) has asymmetrical loss of subcutaneous fat, particularly from the anterior, lateral, and posteriorregions of the thigh and calf, sparing the subcutaneous fat in the medial parts. Reprinted withmodification from Reference 6. Copyright 2005, The Endocrine Society.

G608G mutation in LMNA reveal generalizedlipodystrophy and mild insulin resistance.

Mechanisms of Lipodystrophies

We propose a working hypothesis for the lossof adipose tissue in these disorders, which isbased on our current understanding of the lifecycle of adipocyte. After preadipocytes differ-entiate into mature adipocytes they can un-dergo apoptosis and cell death (Figure 3).The process of adipocyte differentiation andcell death likely continues throughout life.Genetic defects in the BSCL2 gene likelyaffect an early step in the development ordifferentiation of adipose tissue, resulting ingeneralized lipodystrophy. AGPAT2 defectslikely affect differentiation processes down-stream of this step, resulting in sparing ofmechanical adipose tissue depots in patientswith CGL, type 1. Mutations in PPARγ

may also affect terminal differentiation steps.

Because insulin is a key hormone involvedin adipocyte differentiation, disruption ofAKT2, which is a downstream insulin signal-ing molecule, may also affect adipocyte dif-ferentiation. LMNA and ZMPSTE24 muta-tions cause the development of an abnormalnuclear lamina, resulting in premature deathof adipocytes. Alternatively, these genetic de-fects may hinder nuclear transport of specificRNA and proteins, explaining the cell type–specific functional abnormalities seen in thesedisorders.

Phenotypic Variationsin Lipodystrophies

Phenotypic variation occurs at a variety of lev-els. Different mutation(s) in the same genemay alter the activity of the protein or in-terfere differently in the protein-protein orprotein-chromatin interactions and thus mayresult in different phenotypes, as seen in


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patients with LMNA mutations. Phenotypicdifferences are also observed among individ-uals with same mutations. In this regard, in-dividual genetic variation(s) may play a cru-cial role in the development of the phe-notype. Epigenetics, although not so welldefined, suggests that the same genetic in-formation is treated differently within thecell or an organ (65). This might includevariation in chromatin modulation, suchas histone acetyl transferases (HATs) anddeacetylases (HDACs) or histone methyl-transferases (HMTs) or chromatin remodel-ing by SWI/SNF factors (35). The DNAmethylation pattern between two or moresubjects carrying the same mutation could alsoalter the phenotype. Recently, it was shownthat as identical twins grow older, they havedifferent pattern of DNA methylation and hi-stone acetylation, resulting in dissimilar geneexpression (39). Alternatively, in some sub-jects the variation is affected by the maternalinheritance of the mitochondrial DNA alongwith the mutations (73).

Future Challenges

The search for additional loci for the few rareforms of lipodystrophies is complicated by thedifficulty of locating large enough families toperform linkage analysis or sufficent num-bers of unrelated individuals to use linkagedisequilibrium. The present strategy has beento sequence candidate genes known to playcritical roles in adipocyte development, dif-ferentiation or maintenance or in genes thatcause lipodystrophy when they are inactivatedor overexpressed in mice.

Other approaches to identify other geneticdefects causing recessive forms of lipodystro-phy have been to use global transcriptional

(cDNA chip) or protein (proteomics) analy-sis in cells and tissues from affected subjects,parents, and siblings (51). Detecting changesin the protein expression might reveal/reflectperturbation of the cellular pathway involved.Although the analysis of cDNA expressionusing chips is getting better and cheaper,the proteomic approach still needs significantimprovements in automation and analysis,requiring development of tools to analyze hy-drophobic and/or membrane proteins. Dis-covering additional loci may lead us to otherpreviously unrecognized pathways involved inthe development and maintenance of adiposetissues. Furthermore, as suggested recently, a“syndrome family” approach was successfullyapplied for determining loci for skeletal dys-plasias (19), and may also be useful for geneticlipodystrophies.

Our understanding of the mechanisms in-volved in various types of lipodystrophies mayassist in devising strategies for clinical man-agement of these patients (9). We still strug-gle with controlling the metabolic complica-tions associated with lipodystrophy. A recenttwo-center collaborative trial demontratedthat leptin replacement therapy markedlyimproved glycemic control and hypertriglyc-eridemia in hypoleptinemic patients with gen-eralized and partial lipodystrophies (72). Be-cause patients with lipodystrophies are rare,conducting clinical trials in these patients totest new treatment modalities is very difficultand will require the establishment of interna-tional clinical research centers. The explosionof knowledge regarding the molecular basis ofvarious types of genetic lipodystrophies willhopefully provide the opportunity to developnew effective therapies to treat this group ofoften debilitating and disfiguring disorders inwhich therapeutic options are very limited.

SUMMARY POINTS

1. Careful phenotyping of the patients with genetic lipodystrophies has defined distinctautosomal recessive and autosomal dominant disorders.

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2. Autosomal recessive, congenital generalized lipodystrophy is caused by defects inAGPAT2 and BSCL2. AGPAT2 encodes 1-acylglycerol-3-phosphate O-acyltransferase2, which is involved in triacylglycerol and phospholipid biosynthesis. BSCL2 encodesseipin, a protein of unknown function.

3. The autosomal recessive, mandibuloacral dysplasia–associated lipodystrophies arecaused by mutations in the LMNA and ZMPSTE24 genes, which encode lamins A andC, integral components of nuclear lamina, and zinc metalloproteinase enzyme, whichis involved in post-translational proteolytic processing of prelamin A, respectively.

4. Autosomal dominant, familial partial lipodystrophies are genetically and phenotyp-ically heterogeneous disorders linked to LMNA, peroxisome proliferator-activatedreceptor γ (PPARG), a transcription factor playing a central role in adipocyte differen-tiation, and AKT2, which encodes a serine/threonine kinase involved in postreceptorinsulin signaling.

5. The molecular basis of lipodystrophies associated with SHORT syndrome and neona-tal progeroid syndrome remains to be elucidated.

6. Additional loci for congenital generalized lipodystrophy, mandibuloacral dysplasia–associated lipodystrophy, as well as for familial partial lipodystrophy have not yet beenidentified.

7. Understanding the underlying molecular mechanisms of genetic lipodystrophies willassist in the development of new therapeutic strategies to treat this class of geneticdisorders.

ACKNOWLEDGMENTS

The authors were supported in part by the National Institute of Health grants R01-DK54387and M01-RR00633 and by the Southwestern Medical Foundation. The authors thank StephenO’Rahilly for providing unpublished images of the proband with AKT2 mutation and MeredithMillay for the graphics.

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Contents ARI 8 August 2006 1:10

Annual Review ofGenomics andHuman Genetics

Volume 7, 2006

Contents

A 60-Year Tale of Spots, Maps, and GenesVictor A. McKusick � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Transcriptional Regulatory Elements in the Human GenomeGlenn A. Maston, Sara K. Evans, and Michael R. Green � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �29

Predicting the Effects of Amino Acid Substitutions on ProteinFunctionPauline C. Ng and Steven Henikoff � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �61

Genome-Wide Analysis of Protein-DNA InteractionsTae Hoon Kim and Bing Ren � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �81

Protein Misfolding and Human DiseaseNiels Gregersen, Peter Bross, Søren Vang, and Jane H. Christensen � � � � � � � � � � � � � � � � � � � � � 103

The Ciliopathies: An Emerging Class of Human Genetic DisordersJose L. Badano, Norimasa Mitsuma, Phil L. Beales, and Nicholas Katsanis � � � � � � � � � � � � � 125

The Evolutionary Dynamics of Human Endogenous RetroviralFamiliesNorbert Bannert and Reinhard Kurth � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 149

Genetic Disorders of Adipose Tissue Development, Differentiation,and DeathAnil K. Agarwal and Abhimanyu Garg � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 175

Preimplantation Genetic Diagnosis: An Overview of Socio-Ethicaland Legal ConsiderationsBartha M. Knoppers, Sylvie Bordet, and Rosario M. Isasi � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 201

Pharmacogenetics and Pharmacogenomics: Development, Science,and TranslationRichard M. Weinshilboum and Liewei Wang � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 223

Mouse Chromosome Engineering for Modeling Human DiseaseLouise van der Weyden and Allan Bradley � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 247

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Contents ARI 8 August 2006 1:10

The Killer Immunoglobulin-Like Receptor Gene Cluster: Tuning theGenome for DefenseArman A. Bashirova, Maureen P. Martin, Daniel W. McVicar,and Mary Carrington � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 277

Structural and Functional Dynamics of Human CentromericChromatinMary G. Schueler and Beth A. Sullivan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 301

Prediction of Genomic Functional ElementsSteven J.M. Jones � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 315

Of Flies and Man: Drosophila as a Model for Human Complex TraitsTrudy F.C. Mackay and Robert R.H. Anholt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 339

The Laminopathies: The Functional Architecture of the Nucleus andIts Contribution to DiseaseBrian Burke and Colin L. Stewart � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 369

Structural Variation of the Human GenomeAndrew J. Sharp, Ze Cheng, and Evan E. Eichler � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 407

Resources for Genetic Variation StudiesDavid Serre and Thomas J. Hudson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 443

Indexes

Subject Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 459

Cumulative Index of Contributing Authors, Volumes 1–7 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 477

Cumulative Index of Chapter Titles, Volumes 1–7 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 480

Errata

An online log of corrections to Annual Review of Genomics and Human Genetics chaptersmay be found at http://genom.annualreviews.org/

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Genetic Disorders of Adipose Tissue Development, Differentiation, and Death

Documents

Transcript of Genetic Disorders of Adipose Tissue Development, Differentiation, and Death