Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation

Abstract

Particular forms of polycystic ovary syndrome with severe hyperandrogenism, acanthosis nigricans, and marked insulin resistance, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations. However, the majority of affected individuals do not have such mutation, arguing for the genetic heterogeneity of this syndrome. The familial partial lipodystrophy of the Dunnigan type, one of the diseases due to mutations in the lamin A/C (LMNA) gene, is characterized by a lipodystrophic phenotype and shares some clinical and metabolic features with the type A syndrome. We describe here the case of a nonobese 24-year-old woman affected with type A syndrome without clinical lipodystrophy. We linked this phenotype to a novel heterozygous missense mutation in the LMNA, predicting a G602S amino acid substitution in lamin A. This mutation cosegregated with impaired glucose tolerance, insulin resistance, and acanthosis nigricans in the absence of clinical lipodystrophy in the family. The skin fibroblasts from the proband exhibited nuclear alterations similar to those described in other laminopathies, and showed several defects in the insulin transduction pathway. This study further extends the vast range of diseases linked to LMNA mutations and identifies another genetic cause for the type A insulin resistance syndrome. Diabetes 54:1873-1878, 2005 P olycystic ovary syndrome (PCOS) is the most common endocrine abnormality in women of reproductive age and the main cause of anovulatory infertility (1). It is associated with hyperandrogenemia, metabolic alterations including insulin resistance, and an increased risk of type 2 diabetes and cardiovascular disease. The primary cause of PCOS remains elusive, although there is evidence that genetic factors have an important role (2). Particular forms of PCOS with acanthosis nigricans, severe insulin resistance, and hyperandrogenism, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations (3). However, many affected individuals do not have such a mutation, which lends support to the genetic heterogeneity of this syndrome (4).Lamins are the main components of the nuclear lamina, a filamentous network located between inner nuclear membrane and chromatin that plays a fundamental role in nuclear organization in all differentiated cells (5). Mutations in lamins A and C, which are alternatively spliced products of the lamin A/C (LMNA) gene, are responsible for several genetic diseases, including familial partial lipodystrophy of the Dunnigan type (FPLD) (5). Women with FPLD often have irregular menses and hyperandrogenemia, as well as severe insulin resistance, dyslipidemia, and atherosclerotic vascular disease (6 -8). These common clinical and metabolic features of FPLD and type A insulin resistance syndrome led us to search for mutations of the LMNA gene in a patient with a typical type A phenotype.We describe the case of a nonobese 24-year-old woman with severe hyperandrogenemia who had clinical, hormonal, and morphological ov...

Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin

“…The cases described here, similarly to that described previously by Young et al (29), illustrate clearly that monogenic insulin resistance caused by a primary defect in adipose tissue development and function, like insulin resistance caused by primary insulin signalling defects, may produce PCOS. Indeed, hyperandrogenism and oligomenorrhoea are the commonest reasons for presentation to a medical practitioner of patients with monogenic insulin resistance, and careful clinical examination for acanthosis nigricans or abnormal adipose tissue topography are key components of the initial evaluation of any patient with PCOS.…”

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

“…9696 c.746G>A 4 p.R249Q Missense Coil 2a (Benedetti, et al, 2007;Ki, et al, 2002;Muchir, et al, 2004;Raffaele Di Barletta, et al, 2000;Rudenskaya, et al, 2008;Vytopil, et al, 2003) (Onishi, et al, 2002) 2570 c.1072G>A 6 p.E358K Missense Coil 2b (Benedetti, et al, 2007;Mercuri, et al, 2004;Quijano-Roy, et al, 2008) (Benedetti, et al, 2007;Bonne, et al, 1999;Brette, et al, 2004;Colomer, et al, 2002;Fidzianska and Glinka, 2006;Golzio, et al, 2007;Muchir, et al, 2004;Raffaele Di Barletta, et al, 2000;Vytopil, et al, 2003) (Arbustini, et al, 2005) 7288 c.1580G>C 9 p.R527P Missense Tail (Ig-fold) (Benedetti, et al, 2007;Bonne, et al, 1999;Raffaele Di Barletta, et al, 2000;van der Kooi, et al, 2002) 1527 c.1583C>A 9 p.T528K Missense Tail (Ig-fold) (Benedetti, et al, 2007;Fokkema, et al, 2005;Raffaele Di Barletta, et al, 2000) 1200 c.1583C>G 9 p.T528R Missense Tail (Ig-fold) (Fokkema, et al, 2005;Vytopil, et al, 2003) (Bakay, et al, 2006;Young, et al, 2005) 51 c.1930C>T 11 p.R644C Missense Tail (Lamin A specific) (Csoka, et al, 2004;Genschel, et al, 2001;Mercuri, et al, 2005;Muntoni, et al, 2006;Pasotti, et al, 2008;…”

Dunnigan-Type Familial Partial Lipodystrophy: Understanding and Treating the Syndrome

“…In fact, it has been suggested that lipodystrophies are etiologically linked to polycystic ovary syndrome [17] and, in isolated publications, to some obstetric complications [18]. In milder forms of the disease, the phenotype may be indistinguishable from the regular metabolic syndrome.…”