Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy

Abstract

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome

“…1), which encodes the protein seipin whose function was unknown. Mutations in BSCL2 were previously reported to cause autosomal recessive Berardinelli-Seip congenital lipodystrophy type 2, a disorder clinically unrelated to dHMN and Silver syndrome 5,7 . Affected individuals of the Austrian families (F01-F04, F08-F15), the Italian family (F16) and the English families (F07, F17) were heterozygous with respect to a 263A→G transition mutation leading to the amino acid change N88S, whereas those of the Belgian family (F05) and the Brazilian family (F06) were heterozygous with respect to a 269C→T (S90L) missense mutation.…”

A Patient with Congenital Generalized Lipodystrophy Due To a Novel Mutation in BSCL2: Indications for Secondary Mitochondrial Dysfunction

“…Lipids are stored aberrantly in muscle and liver resulting in extreme insulin resistance. In addition to hepatomegaly and generalized muscular hypertrophy, patients have acromegaloid features such as enlarged hands and feet, acanthosis nigricans, and excessive body hair (Garg 2004;Van Maldergem et al 2002). A significant number of patients develop hypertrophic cardiomyopathy (HCM) (Van Maldergem et al 2002;Agarwal et al 2003).…”

Pathology of Congenital Generalized Lipodystrophy in Agpat2–/– Mice

“…23 Affected humans usually develop insulin-resistant lipoatrophic diabetes during adolescence. 53 BSCL has been linked to genetic mutations affecting 2 proteins: the lipid biosynthetic enzyme 1-acyl-sn-glycerol 3-phosphate O-acyltransferase 2 (AGPAT2) in type 1 CGL 2 and the integral endoplasmic reticulum membrane protein seipin in type 2 CGL. 35 The AGPAT2 enzyme represents 1 of at least 10 isoforms of AGPAT, all of which have different tissue expression profiles.…”