Divergent Metabolic Phenotype between Two Sisters with Congenital Generalized Lipodystrophy Due to Double AGPAT2 Homozygous Mutations. A Clinical, Genetic and In Silico Study

Cortés, Víctor A.; Smalley, Susan V.; Goldenberg, Denisse; Lagos, Carlos F; Hodgson, María I.; Santos, Jose L.; Moro, Cedric

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.

Más información

Título según WOS: Divergent Metabolic Phenotype between Two Sisters with Congenital Generalized Lipodystrophy Due to Double AGPAT2 Homozygous Mutations. A Clinical, Genetic and In Silico Study
Título según SCOPUS: Divergent metabolic phenotype between two sisters with congenital generalized lipodystrophy due to double AGPAT2 homozygous mutations. A clinical, genetic and in silico study
Título de la Revista: PLOS ONE
Volumen: 9
Número: 1
Editorial: PUBLIC LIBRARY SCIENCE
Fecha de publicación: 2014
Idioma: English
URL: http://dx.plos.org/10.1371/journal.pone.0087173
DOI:

10.1371/journal.pone.0087173

Notas: ISI, SCOPUS