Divergent metabolic phenotype between two sisters with congenital generalized lipodystrophy due to double AGPAT2 homozygous mutations. a clinical, genetic and in silico study.
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.
Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Víctor A
VA
Cortés
Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Susan V
SV
Smalley
Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Denisse
D
Goldenberg
Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Carlos F
CF
Lagos
Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
María I
MI
Hodgson
Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
José L
JL
Santos
D000217:Acyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D020738:Leptin / Q000097:blood / Q000378:metabolism; D052497:Lipodystrophy, Congenital Generalized / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D054411:Receptors, Leptin / Q000378:metabolism; D035781:Siblings
D020738:Leptin; D054411:Receptors, Leptin; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase