Abstract
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations.
Highlights
Congenital generalized lipodystrophy (CGL) or BerardinelliSeip syndrome (OMIM # *608594) is an infrequent autosomal recessive disorder characterized by severe reduction of whole body white adipose tissue (WAT) mass
Neither pSer100N substitution nor p.165Leu to p.196Gln deletion was expected to change AGPAT2 folding. This is the first report of Chilean patients with congenital generalized lipodystrophy
It is noteworthy that total circulating leptin levels are lower and soluble leptin receptor levels are higher in the subject with the most severe phenotype
Summary
Congenital generalized lipodystrophy (CGL) or BerardinelliSeip syndrome (OMIM # *608594) is an infrequent autosomal recessive disorder characterized by severe reduction of whole body white adipose tissue (WAT) mass. CGL-1 is caused by mutations in AGPAT2 gene [4] and is characterized by profound reduction of subcutaneous and visceral WAT. CGL2 is caused by mutations in BSCL2 gene [5] and is the most severe form of generalized lipodystrophy. These patients have virtual absence of both WAT and mechanical fat depots and frequently develop mild to moderate intellectual impairment [6]
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