Heterogeneidade fenotípica da Lipodistrofia Generalizada Congênita do Tipo 1: uma análise de genótipo-fenótipo das principais variantes patogênicas em AGPAT2 relatadas no Brasil

Abstract

The encoding gene AGPAT2 gives rise to the protein 1- AGPAT2, which is 31kDa and contains 278 amino acids. It has 4 transmembrane domains and is located in the endoplasmic reticulum (ER). The highly conserved domains of the enzyme are: EGTR, NHXXXXD (NHX4D), FINR and IVPV. Therefore, homozygous or compound heterozygous mutations in the AGPAT2 gene promote the development of patients with Congenital Generalized Lipodystrophy Type 1, an autosomal recessive disease, in which there is a generalized absence of metabolically active adipose tissue since birth. CGL 1 is considered a rare disease, with a significant prevalence in the interior of the state of Rio Grande do Norte (RN), Brazil, where inbreeding is common. Thus, given the significant prevalence of AGPAT2 mutations in Brazil, studies have shown that the main alterations in the gene are: c.299G>A, c.366_588+534del, c.369_372delGCTC, c.589-2A>G, c.570C>A, and c.646A>T, which generate distinct protein consequences. Therefore, this study aims to analyze the genotype-phenotype clarity of pathogenic mutations in AGPAT2 in patients with LGC 1 in Brazil, approaching the analysis of the structure of 1-AGPAT 2 resulting from these mutations. For this purpose, modeling of the three-dimensional structure of 1-AGPAT 2 was performed with the aid of the SWISS-MODEL tool, using the model of the Mus musculus species (Uniprot Q8K3K7), analysis of the mutations searched in ClinVar, and a literature review covering articles published up to 2024 in the Pubmed article database. The analyses demonstrated that most of the alterations compromise the catalytic activity of the enzyme, impairing its proper functioning. The alterations that generated a protein with loss of more than one functional domain presented different phenotypes, in addition to being more severe. Furthermore, most of the pathogenic variants, in addition to losing at least one functional domain, underwent conformational alterations with absence or change of helices and beta sheets, which may interfere with their ideal functioning. Even more detailed studies are needed to better understand the pathogenicity mechanisms of each pathogenic variant, refining the understanding of mutations in AGPAT2 and their consequences on its protein product, 1-AGPAT 2.