genetic syndromes of human lipodystrophy
Genetic Syndromes of Human Lipodystrophy
Shelly Bhayana MD, Robert A. Hegele MD FRCPC
Robarts Research Institute, London, Ontario, Canada
This paper was presented in part at the Canadian Diabetes Association/Canadian Society of Endocrinology and Metabolism
Professional Conference, October 17–20, 2001, Edmonton,Alberta, Canada
A B S T R A C T R É S U M É
Lipodystrophy is characterized in broad terms by loss of sub- La lipodystrophie est grosso modo une perte de tissu adipeux
cutaneous (SC) adipose tissue. Despite heterogeneous causes, sous-cutané. Malgré leurs causes hétérogènes, qui sont à
which include both genetic and acquired forms, lipodystrophy l’origine des formes génétiques et acquises, les syndromes de
syndromes have similar metabolic attributes, including insulin lipodystrophie ont des attributs métaboliques semblables,
resistance, hyperlipidemia and diabetes. Recently, the molecu- dont l’insulinorésistance, l’hyperlipidémie et le diabète.
lar bases of 2 genetic forms of lipodystrophy, namely, Récemment, les bases moléculaires de deux formes géné-
Dunnigan-type familial partial lipodystrophy (FPLD, Online tiques de lipodystrophie, soit la lipodystrophie familiale par-
Mendelian Inheritance in Man [OMIM] #151660) and tielle de Dunnigan (FPLD, banque de données Online
Berardinelli-Seip congenital lipodystrophy (BSCL, OMIM Mendelian Inheritance in Man [OMIM], no 151660) et la
#269700), have been reported.There is evidence for genetic lipodystrophie congénitale de Berardinelli-Seip (BSCL,
heterogeneity for both types of lipodystrophy. Such findings OMIM no 269700) ont été décrites. On a constaté que ces
may have relevance for the common insulin resistance syn- deux types de lipodoystrophie avaient une homogénéité
drome and for acquired lipodystrophy syndromes. génétique. Cette constatation pourrait être liée au syndrome
d’insulinorésistance courant et aux syndromes de lipodystro-
Address for correspondence:
Robert A. Hegele
Blackburn Cardiovascular Genetics Laboratory
Robarts Research Institute
406–100 Perth Drive
N6A 5K8 Canada
Telephone: (519) 663-3461
Fax: (519) 663-3037
E-mail: hegele @ robarts.ca
CANADIAN JOURNAL OF DIABETES. 2002;26(4):363-368.
CANADIAN JOURNAL OF DIABETES
INTRODUCTION extremities and the gluteal region, resulting in prominent,
One approach to understanding a common complex pheno- well-defined musculature (10-12). Excess fat deposition in the
type is to study a genetically extreme form. For instance, face and neck may cause a double chin and fat neck (10-12).
insulin resistance is a common disorder that is often associated Fat may also accumulate in the axillae, back, labia majora and
with a cluster of metabolic abnormalities referred to as “meta- intra-abdominal region (10-12). Because the fat in the neck
bolic syndrome X” or the “insulin resistance syndrome” (1,2). and upper trunk creates an impression of truncal obesity,
The insulin resistance syndrome is frequently observed in FPLD can be misdiagnosed as Cushing’s syndrome. However,
obese individuals and is characterized by impaired glucose plasma glucocorticoid metabolism is normal in patients with
tolerance (IGT), hyperlipidemia and hypertension (1,2), FPLD. Imaging studies have confirmed the lack of SC fat,
which are often present before the onset of frank diabetes with preservation of intermuscular, intra-abdominal,
mellitus. Defining the underlying mechanisms of insulin intrathoracic and bone marrow fat, and excessive intramus-
resistance might help in the development of prevention cular (IM) fat (12). The biochemical hallmark of FPLD is
and/or treatment strategies. Examples of monogenic insulin insulin resistance with hyperinsulinemia. Diabetes often
resistance are provided by patients affected with the genetic develops later in life, and large doses of insulin may be
lipodystrophies, specifically autosomal dominant (AD) par- required. Hyperlipidemia and hypertension are also com-
tial lipodystrophy of the Dunnigan type (familial partial mon. Additional findings variably include acanthosis nigri-
lipodystrophy [FPLD], Online Mendelian Inheritance in Man cans, hirsutism, menstrual abnormalities and polycystic
[OMIM] #151660) and autosomal recessive (AR) complete ovarian disease (10-12).
lipodystrophy of the Berardinelli-Seip type (Berardinelli-Seip
congenital lipodystrophy [BSCL], OMIM #269700). The Molecular genetics of FPLD
genes for these 2 conditions were recently identified using While FPLD is more obvious in women, both sexes are
several genetic mapping approaches, culminating in the iden- equally affected. Furthermore, because normal men may be
tification of rare mutations in affected subjects that specified quite muscular, classifying men can be difficult (10-12).
the causative gene for each disease. Genome-wide scans mapped the FPLD genetic locus to
chromosome 1q21–q22 (13-15). Discovery that the lamin
CLASSIFICATION OF LIPODYSTROPHIES A/C gene (LMNA) was the FPLD gene was accomplished by
Lipodystrophies can be broadly classified into either familial/ sequencing positional candidate genes; LMNA was selected
genetic or acquired types. Each form of lipodystrophy is because it localized within 1q21–q22 and because LMNA
characterized by selective loss of adipose tissue from partic- mutations were found in AD Emery-Dreifuss muscular dys-
ular regions of the body.The extent of fat loss usually deter- trophy (EMD2), which is characterized by regional and pro-
mines the severity of the associated clinical and metabolic gressive degeneration of skeletal and cardiac myocytes (16).
manifestations. Acquired generalized lipodystrophy was Mutations in the LMNA gene were also found in AD dilated
described more than 50 years ago when Lawrence reported a cardiomyopathy (CMD1A) (17) and in AD limb girdle mus-
patient with diabetes who had atrophic fat stores and hyper- cular dystrophy with cardiac conduction abnormalities
lipidemia (3). Acquired partial lipodystrophy is associated (LGMD1B) (18). The analogy between the specificity of the
with a serum immunoglobulin G called complement 3 nephrit- adipocyte wasting in FPLD and the site-specific cellular atro-
ic factor (4), although its association with insulin resistance is phy in EMD2 and CMD1A was the basis for the decision to
variable. Highly active antiretroviral therapy (HAART) for sequence LMNA in Canadian subjects with FPLD (19).
human immunodeficiency virus (HIV) often induces, through Genomic DNA sequencing revealed a nonconservative LMNA
an unknown mechanism, a lipodystrophy syndrome that is mutation, R482Q (OMIM #150330.0010), in 5 FPLD
characterized by peripheral fat wasting and central adiposity, probands (19).The same mutation was found in an apparently
insulin resistance, diabetes and hyperlipidemia (5-7). This unrelated Canadian family (20). Other mutations in LMNA in
review focusses on the recently discovered molecular genet- patients with FPLD have subsequently been identified (21-24).
ic bases of FPLD and BSCL.
Clinical and biochemical phenotypes in FPLD
Dunnigan-type familial partial lipodystrophy Genetic markers for FPLD have eliminated the need to
About 30 years ago, Ozer and colleagues described a woman deduce carrier status clinically. Analysis by genotype indicat-
with fat accumulation on the face, neck, shoulders, axillae, ed that nondiabetic LMNA Q482/R482 heterozygotes had
back and genitalia, but an absence of limb fat (8). Similarly higher plasma concentrations of TGs, insulin and C-peptide,
affected subjects had diabetes and elevated plasma triglyc- and lower high-density lipoprotein cholesterol (HDL-C)
erides (TGs) (9). Kobberling and Dunnigan also described than genetically normal family controls (25). Furthermore,
families with this form of lipodystrophy, which is now known LMNA Q482/R482 heterozygotes with diabetes had even
as FPLD (10). Patients with FPLD are normal at birth, but higher plasma concentrations of TGs, insulin and C-peptide,
during puberty they lose subcutaneous (SC) fat from the and lower HDL-C than nondiabetic heterozygotes (25).
genetic syndromes of human lipodystrophy
These findings suggest that glycemia is under stricter meta- The mutations associated with FPLD might also have effects
bolic control than plasma lipoproteins at earlier stages of the in other tissues; for example, the mutations might cause
disease. Importantly, this cluster of metabolic abnormalities insulin resistance by an unrelated mechanism in the liver or
in carriers of mutant LMNA with diabetes was associated with muscle. A complicating attribute in FPLD is that puberty
accelerated atherosclerosis (26). LMNA Q482/R482 het- triggers the adipocyte loss, indicating that hormonal changes
erozygotes also had significantly lower plasma leptin than provoke disease expression in carriers of mutant LMNA. Such
unaffected R482/R482 subjects, with the LMNA R482Q complexity observed in the whole person might overwhelm
genotype accounting for ≈50% of the attributable variation the capacity of in vitro cell biological assays of lamin interac-
in leptin (27). Whether the lower leptin levels result from tions with other laminar proteins to fully explain the pheno-
reduced adipose mass in patients with FPLD or from anoth- typic changes observed in FPLD. Other in vitro assays of
er subcellular effect of mutations in LMNA remains to be lamin A function might be required.
Berardinelli-Seip congenital lipodystrophy
What do the LMNA disease mutations tell us? In 1954, Berardinelli described 2 children, aged 2.5 and
Nuclear lamins are intermediate filament proteins that par- 6 years, with muscular hypertrophy, hepatosplenomegaly,
ticipate in DNA replication, chromatin organization, spatial acromegaloid features, hyperlipidemia and abnormal carbo-
arrangement of nuclear pores, nuclear growth and anchorage hydrate metabolism (33). Because of additional characteriza-
of nuclear membranes (28-30). In non-dividing cells, compo- tion by Seip (34,35), the condition is now called
nents of the nuclear envelope mediate bi-directional molecu- Berardinelli-Seip congenital lipodystrophy (BSCL). In con-
lar traffic between the cytoplasm and the nucleus (28-30). trast to FPLD, in which patients appear normal at birth, the
Alternate splicing at exon 10 of LMNA provides sequence overall paucity of adipose tissue and the muscular hypertro-
identity for the first 566 residues of lamins A and C, with dis- phy in BSCL are evident from birth (33). Magnetic resonance
tinctive C-termini (28). Lamins A and C polymerize to form imaging (MRI) studies in patients with BSCL have confirmed
part of the nuclear lamina, a meshwork of 10 nm filaments a negligible amount of fat in intra-abdominal and intratho-
on the inner surface of the nuclear envelope (28-30). Both racic areas, and in bone marrow (36). Interestingly, imaging
lamin isoforms are coexpressed in terminally differentiated studies have also detected fat in sites such as orbits, palms,
cells (28-30). Lamins A and C have globular head and tail soles, peri-articular and epidural regions, breasts, tongue,
domains and a central rod domain (28). Hydrophobic vulva and buccal area, suggesting preservation of “mechani-
residues in the rod domains promote dimerization, and sur- cal” adipose tissue in these patients (36).
face charges orient the filaments in the lattice. In addition to the repartitioning of adipose tissue, subjects
Three FPLD mutations alter LMNA codon 482 (19-24), with BSCL have other notable clinical features, including
suggesting a precise relationship between the position of the acromegaloid features, such as increased size of hands, feet
mutation and the biological outcome. The position of the and mandible, that are present in infancy and childhood, and
mutant residue within LMNA appears to be a crucial deter- radiographic evidence of advanced bone age (33,34,37).
minant of both the type and the anatomical distribution of There is an apparent overall increase in anabolism, with
the affected cells, suggesting a high degree of functional increased appetite, increased growth velocity and adult
specificity for lamin residues. LMNA disease mutations could height ranging from normal to 2 standard deviations (SDs)
destabilize lamin multimers and disrupt the nuclear lamina, above normal (33,37). The basal metabolic rate in BSCL is
which may selectively affect adipocytes because of different increased, ranging from 1.2- to 1.8-fold of normal.
tissue expression of redundant proteins. Alternatively, Hyperhidrosis can be quite pronounced after puberty (37).
mutant lamin may have impaired interactions with chro- Bony abnormalities can also develop, with initial sclerotic
matin, nuclear membrane proteins, transcription factors changes progressing to focal bony lesions and cysts (38-40).
and/or other cellular proteins. A function lost through an Hepatosplenomegaly and lymphadenopathy are often pres-
LMNA mutation could be rescued by other proteins (31). ent. Autopsy findings have also shown liver enlargement sec-
Differential tissue expression of lamins and associated pro- ondary to fatty infiltrate; this process may cause progression
teins might alter the impact of mutations in LMNA. Lamin to cirrhosis and end stage renal disease (ESRD) (34). Females
might also interact with transcription factors, such as sterol with BSCL may suffer from hirsutism, along with cli-
regulatory element binding protein-1c (SREBP-1c), provid- toromegaly, oligomenorrhea, polycystic ovaries and reduced
ing a link between lipodystrophy occurring in humans with fertility. Most males will have normal reproduction. Other
mutations in LMNA and in mice transgenic for SREBP-1c. In associated features include mental retardation and hypothal-
FPLD, the cellular consequences of mutations in LMNA might amic-pituitary dysfunction.There are some reports of hyper-
decrease adipose tissue mass through impairment of pre- trophic cardiomyopathy in patients with BSCL, with
adipocyte proliferation and/or differentiation of mature evidence of both symmetrical and asymmetrical hypertro-
adipocytes, in addition to modulation of apoptosis (31,32). phy, and normal myocyte arrangement on autopsy (41-45).
CANADIAN JOURNAL OF DIABETES
The main biochemical abnormality in BSCL is resistance in this study experienced hepatotoxicity related to the study
to both endogenous and exogenous insulin (39). Extreme medication (52).Therefore,TZD therapy appeared to improve
hyperinsulinemia and hyperlipidemia, with high TGs and low metabolic control and increase body fat in patients with FPLD.
HDL-C, may be observed as early as in infancy.This can often These effects may be related to the ability of TZDs to stimu-
be complicated by chylomicronemia, eruptive xanthomas late adipocyte differentiation, or to the improved metabolic
and acute pancreatitis (36). Diabetes may develop during control with resulting reduction of glycosuria and sparing of
puberty or early adolescence. A proposed mechanism is the body fat (52). These promising preliminary results must be
gradual failure of beta cells and subsequent impairment of confirmed in larger and longer-term trials that also evaluate
glucose tolerance. Islet cell amyloidosis resulting from treatment with rosiglitazone (Avandia®) and pioglitazone
chronic overstimulation of insulin secretion is a possible (Actos®) in order to determine if the possible benefits of treat-
mechanism for beta cell destruction (46). ment and risk of hepatotoxicity represent a class effect. In a
more recent study, leptin-replacement therapy improved
Genetics of BSCL glycemic control and decreased TG levels in patients with
A genome-wide scan in 1999 using 17 well-defined BSCL lipodystrophy and leptin deficiency, suggesting that leptin defi-
families mapped the BSCL locus to chromosome 9q34 ciency contributes to insulin resistance and other metabolic
(BSCL1) (47). This critical region contains the gene for abnormalities in lipodystrophy (53).
retinoid X receptor alpha (RXRA), which plays a central role
in adipocyte differentiation; however, no mutations in RXRA CONCLUSION
have yet been found (48). Interestingly, a subset of European The demonstration of disease mutations in FPLD and BSCL
(from the United Kingdom [UK] and Turkey) BSCL pedi- introduces new mechanisms for study in the development of
grees did not show linkage to this locus. Homozygosity map- lipodystrophy, as well as insulin resistance with its attendant
ping in BSCL families from Lebanon and Norway linked the clinical and metabolic complications.The present challenges
disease to a different locus, designated BSCL2, on chromo- include understanding how these mutations cause the respec-
some 11q13 (49). Using microsatellite markers, the region tive diseases and their downstream complications, and using
for this locus was narrowed, and a total of 13 mutations in a this information in the development of new therapies. For
novel gene were identified amongst the 44 patients studied. instance, studies in transgenic mice suggest that continuous
The predicted protein of BSCL2, “seipin,” is expressed primari- leptin administration or direct implantation of adipose tissue
ly in the brain and testes (49). Its structure includes several may reverse the loss of adipose tissue and the metabolic
hydrophobic regions, suggesting its possible role as a trans- changes associated with lipodystrophy. Furthermore, the
membrane protein. Interestingly, the BSCL2 region is analogous apparently beneficial effect of TZDs in patients with lipodys-
to a region on rat chromosome 1 that contains loci involved in trophy indicates that these agents may also reverse the loss of
metabolic and phenotypic alterations of diabetes (49). Of the adipose tissue and metabolic changes. It is unlikely, however,
families examined in this study, only 9 were found to show link- that gene therapy for FPLD will become a reality in the near
age to the previously described locus on chromosome 9q34, future because of the high degree of tissue specificity, the
while 13 families showed linkage to BSCL2 on chromosome unknown hormonal or metabolic trigger(s), and the absence
11q13, suggesting genetic heterogeneity for the phenotype. of insight into the cellular mechanism of the disease. Finally,
the knowledge that a defective structure of the nuclear enve-
THIAZOLIDINEDIONES, LEPTIN AND lope is involved in FPLD may lead to new target pathways for
LIPODYSTROPHY the assessment and treatment of lipodystrophy.
Thiazolidinediones (TZDs) promote adipocyte differentia-
tion in vitro and increase insulin sensitivity in vivo (50,51). ACKNOWLEDGEMENTS
Because of these mechanisms of action, TZDs theoretically Robert A. Hegele holds the Canada Research Chair (Tier 1) in
may have a therapeutic benefit in FPLD. A 6-month, open- Human Genetics and a Career Investigator award from the
label, prospective study evaluated treatment with troglita- Heart and Stroke Foundation of Ontario. General support was
zone at doses ranging from 200 to 600 mg/day in 7 patients provided by grants from Canadian Institutes for Health Research
with FPLD, as well as in subjects with other lipodystrophy (MT13430), the Canadian Diabetes Association (in honour of
syndromes (52). The authors noted improvement in meta- Hazel E. Kerr) and the Canadian Genetic Diseases Network.
bolic indices, including reduced HbA1c, fasting TG levels and
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