Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations

Autor(es)

Varela, Patricia ^[1] ; Carvalho, Gerson ^[2] ; Martin, Renan Paulo ^{[1, 3]} ; Pesquero, Joao Bosco ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Biophys, Ctr Res & Mol Diagnost Genet Dis, Rua Pedro Toledo 669, 9o Andar, BR-04039032 Sao Paulo - Brazil

^[2] Hosp Apoio Brasilia, Med Genet Unit, Brasilia, DF - Brazil

^[3] Johns Hopkins Univ, Sch Med, McKusick Nathans Dept Genet Med, Baltimore, MD - USA

• Tipo de documento: Artigo Científico
• Fonte: METABOLIC BRAIN DISEASE; v. 36, n. 2 NOV 2020.
• Citações Web of Science: 0

Resumo

Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding alpha-galactosidase A, an enzyme required for degradation of glycosphingolipids, mainly globotriaosylceramide (Gb3) in all cells of the body. FD patients present a broad spectrum of clinical phenotype and many symptoms are shared with other diseases, making diagnosis challenging. Here we describe a novel GLA variant located in the 5 ` splice site of the intron 3, in four members of a family with neuropsychiatric symptoms. Analysis of the RNA showed the variant promotes alteration of the wild type donor site, affecting splicing and producing two aberrant transcripts. The functional characterization showed absence of enzymatic activity in cells expressing both transcripts, confirming their pathogenicity. The family presents mild signs of FD, as angiokeratoma, cornea verticillata, acroparesthesia, tinnitus, vertigo, as well as accumulation of plasma lyso-Gb3 and urinary Gb3. Interestingly, the man and two women present psychiatric symptoms, as depression or schizophrenia. Although psychiatric illnesses, especially depression, are frequently reported in patients with FD and studies have shown that the hippocampus is an affected brain structure in these patients, it is not clear whether the Gb3 accumulation in the brain is responsible for these symptoms or they are secondary. Therefore, new studies are needed to understand whether the accumulation of Gb3 could produce neuronal alterations leading to psychiatric symptoms. (AU)

• Processo FAPESP: 14/27198-8 - Estabelecimento de um centro de pesquisa genética e molecular para desafios clínicos
• Beneficiário: João Bosco Pesquero
• Modalidade de apoio: Auxílio à Pesquisa - Temático