Phenotypic Gender Differences in Subjects With Familial Partial Lipodystrophy (Dunnigan Variety) Due to a Nuclear Lamin A/C R482W Mutation

Abstract

Phenotypic features appeared after puberty in female, but not male subjects with familial partial lipodystrophy (FPLD). We have studied anthropometrical, clinical, and metabolic gender differences in a Spanish family with FPLD resulting from a lamin A/C gene mutation, R482W. Genetic studies were carried out on 14 members of the family. In eleven heterozygous mutation carriers (6 men, 5 women), body composition was evaluated by bioelectric impedance analysis, skin-fold measurements were taken, and lipid profiles were drawn. Moreover, plasma glucose, insulin, and leptin were determined, and insulin resistance and beta cell response were evaluated using HOMA. Ten healthy women and 10 healthy men matched for age and body mass index were used as control group. Body composition was similar in these patients to normal people. However, skin-folds of extremities were thinner in FPLD women compared with those of control subjects, but not in men. The affected women, but not men, showed hypoleptinaemia, insulin resistance, and beta-cell hyperresponse compared with unaffected women. The lipid profile was normal in the young patients, irrespective of sex. Type 2 diabetes mellitus and hypertriglyceridaemia were detected in old and overweight patients only. In conclusion, molecular diagnosis allows us to demonstrate that women with FPLD present both adipose tissue and biochemical abnormalities early in life, and this did not happen in affected men.

LMNA Gene - Subcutaneous Adipose Tissue - Insulin Resistance - Leptin - Body Composition - Lipid Profile

References

• 1 Dunnigan M G, Cochrane M A, Kelly A, Scott J W. Familial lipoatrophic diabetes with dominant transmission.  Quartely Journal of Medicine. 1974;  43 33-48
• 2 Davidson M B, Young R T. Metabolic studies in familial partial lipodystrophy of the lower trunk and extremities.  Diabetologia. 1975;  11 561-568
• 3 Ursich M JM, Fukui R T, Galvâo M SA. et al . Insulin resistance in limb and trunk partial lipodystrophy (type 2 Köbberling-Dunnigan syndrome).  Metabolism. 1997;  46 159-163
• 4 Hegele R A, Anderson C M, Wang J, Jones D C, Cao H. Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipemia, hypertension and diabetes.  Genome Research. 2000;  10 652-658
• 5 Hegele R A. Premature atherosclerosis associated with monogenic insulin resistance.  Circulation. 2001;  103 2225-2229
• 6 Cao H, Hegele R A. Nuclear lamin A/C R482Q mutation in Canadian kindred with Dunnigan-type familial partial lipodystrophy.  Human Molecular Genetics. 2000;  9 109-112
• 7 Speckman R A, Garg A, Du F. et al . Mutational and haplotype analyses of families with partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C.  Am J Hum Gent. 2000;  66 1192-1198
• 8 Shackleton S, Lloyd D J, Jackson S N. et al . LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.  Nat Gent. 2000;  24 153-156
• 9 Vigouroux C, Magré J, Vantyghem M C. et al . Lamin A/C gen. Sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy.  Diabetes. 2000;  49 1958-1962
• 10 Garg A, Peshock R M, Fleckenstein J L. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety).  J Clin Endocrinol Metab. 1999;  84 170-174
• 11 World Medical Association Declaration of Helsinki .Ethical principles for medical research involving human subjects. Bull. WHO 2001 79: 373-374
• 12 Segal K R, van Loan M, Fitzgerald P I, Hodgdon J A, van Itallie T B. Lean body mass estimation by bioelectrical impedance analysis: a four-site cross-validation study.  Am J Clin Nutr. 1998;  47 7-14
• 13 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentration in man.  Diabetologia. 1985;  28 412-419
• 14 Weyer C, Wolford J K, Hanson R L. et al . Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21 - 23 and is associated with common polymorphism in LMNA in Pima Indians.  Mol Genet Metab. 2001;  72 231-238
• 15 Hegele R A, Cao H, Harris S B, Zinman B, Hanley A J, Anderson C M. Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians.  Physiol Genomics. 2000;  3 39-44
• 16 Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety).  J Clin Endocrinol Metab. 2000;  85 1776-1782
• 17 Ozer F L, Lichtenstein R M, Kwiterovich P O, McKusick V A. A new genetic variety of lipodystrophy.  Clin Res. 1973;  21 533
• 18 Kobberling J, Dunnigan M G. Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state.  J Med Genet. 1986;  23 120-127
• 19 Burn J, Baraitser M. Partial lipoatrophy with insulin resistant diabetes and hyperlipidaemia (Dunnigan variety).  J Med Genetics. 1986;  23 128-130
• 20 Lillystone D, West R J. Lipodystrophy of limbs associated with insulin resistance.  Arch Dis Child. 1975;  50 737-739
• 21 Schmidt H HJ, Genschel J, Baier P. et al . Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene.  J Clin Endocrinol Metab. 2001;  86 2289-2295
• 22 Oral E A, Simha V, Ruiz E. et al . Leptin-replacement therapy for lipodystrophy.  N Engl J Med. 2002;  346 570-578
• 23 Hegele R A, Cao H, Huff M W, Anderson C M. LMNA R482Q mutation in partial lipodystrophy associated with reduced plasma leptin concentration.  J Clin Endocrinol Metab. 2000;  85 3089-3093
• 24 Wajchenberg B L. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome.  Endocrine Rev. 2000;  21 697-738
• 25 Tchernof A, Després J-P. Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women.  Horm Metab Res. 2000;  32 526-536
• 26 Garg A, Speckman R A, Bowcock A M. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene.  Am J Med. 2002;  112 549-555