Berardinelli-Seip congenital lipoatrophy type 1 (BSCL1) is a rare autosomal recessive disease caused by mutations in the AGPAT2 gene. This syndrome is characterized by near total absence of adipose tissue since birth, associated with the progressive development of metabolic complications. The AGPAT2 gene encodes for 1-acylglycerol-3phosphate-O-acyltransferase highly expressed in white adipocytes that catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. Close to 95% of patients affected by BSCL have identified mutations. Most of the homozygous or compound heterozygous mutations reported in BSCL patients cause frame-shifts, insertions, deletions or alter the splicing determining a nonfunctional enzyme, fewer cause amino acid substitutions. We describe the case of a 53 years old woman referred to our Center for a suspicion of BSCL. She was born from consanguineous parents (second-degree cousins) and diagnosed at 10 years with lipoatrophic diabetes and hypertriglyceridemia. Over the years, diabetes control was poor and she developed bilateral proliferative retinopathy and diabetic-hypertensive nephropathy. At the time we first visited her, she had striking acromegaloid features, diffuse lipoatrophy, muscolar pseudo-hypertrophy and a small umbilical hernia. BSCL1 syndrome was confirmed after the detection of a double homozygote gene mutation leading to the substitution of the residue Serine at position 61 with an Arginine (S61R) and substitution of the Arginine residue at position 159 with a Cysteine (R159C). The intriguing combination of two different homozygotes missense mutations never described previously, raised the question on which of the two mutations was likely to be causing the disease. The mutation Ser61Arg results in an aminoacid change at evolutionary non-conserved sites. The mutation was also present as homozygote in the unaffected brother. The mutation Arg159Cys affects a conserved aminoacid site and resides in a highly conserved region among mammalian species. This substitution was present in the heterozygote state in the unaffected brother. In this case the homozygote mutation segregated with the disease and the in silico score was predictive of disruption, making its pathogenic role likely. In conclusion we describe a novel missense AGPAT2 mutation (R159C) which is responsible for BSCL1.
18 - 21 May 2019
European Society of Endocrinology