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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1006-1013
Copyright © 2003 by The Endocrine Society

A New Clinical Condition Linked to a Novel Mutation in Lamins A and C with Generalized Lipoatrophy, Insulin-Resistant Diabetes, Disseminated Leukomelanodermic Papules, Liver Steatosis, and Cardiomyopathy

F. Caux, E. Dubosclard, O. Lascols, B. Buendia, O. Chazouillères, A. Cohen, J.-C. Courvalin, L. Laroche, J. Capeau, C. Vigouroux and S. Christin-Maitre

Service de Dermatologie, Hôpital Avicenne (F.C., L.L.), 93000 Bobigny; Département de Biologie Cellulaire, Institut Jacques Monod, UMR 7592 (B.B., J.-C.C.), 75005 Paris; and UPRES EA-3408, Université Paris XIII (F.C., L.L.); INSERM, U-402, Faculté de Médecine Saint-Antoine (E.D., O.L., C.V.), Laboratoire de Biologie Moléculaire, Fédération de Biochimie (O.L.), Service d’Hépatologie (O.C.), Service de Cardiologie (A.C.), Service d’Endocrinologie, EA 1533 Génétique de la Reproduction Humaine (S.C.-M.), Hôpital Saint-Antoine, 75012 Paris, France

Address all correspondence and requests for reprints to: Dr. Sophie Christin-Maitre, Service d’Endocrinologie, Hôpital Saint-Antoine, 184 rue du Fbg Saint-Antoine, 75571 Paris Cedex 12, France. E-mail: sophie.christin-maitre{at}sat.ap-hop-paris.fr.

A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive.

We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient’s cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations.

This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.

This work was supported by grants from INSERM, Centre National de la Recherche Scientifique, Direction de la Recherche Clinique Assistance Publique-Hôpitaux de Paris, and the Association pour la Recherche sur le Cancer.

Abbreviations: CMT2B1, Autosomal recessive Charcot-Marie-Tooth disease type 2; DAPI, 4',6-diamidine-2'-phenylindole-dihydrochloride; DCM-CD, dilated cardiomyopathy with conduction defects; EDMD, Emery-Dreifuss muscular dystrophy; FPLD, familial partial lipodystrophy of the Dunnigan type; LGMD1B, limb-girdle muscular dystrophy type 1B; LV, left ventricular; mab, monoclonal antibody; MAD, mandibuloacral dysplasia.




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