Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations
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ORIGINAL ARTICLE
Fabry disease: GLA deletion alters a canonical splice site in a family with neuropsychiatric manifestations Patrícia Varela 1 & Gerson Carvalho 2 & Renan Paulo Martin 1,3 & João Bosco Pesquero 1 Received: 12 August 2020 / Accepted: 30 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Fabry disease (FD) is a rare X-linked glycosphingolipidosis caused by mutations in GLA, a gene responsible for encoding αgalactosidase 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. Keywords Fabry disease . Splice site mutation . α-Galactosidase A . Psychiatric symptoms, GLA gene . Neurological manifestations . Depression . Schizophrenia
Introduction Fabry Disease (FD, OMIM # 301500) is a rare and progressive X-linked glycosphingolipidosis. The origin of the disease is attributed to pathogenic mutations in the GLA, a gene responsible for encoding the α-galactosidase A enzyme (α-Gal A; EC 3.2.1.22). The deficiency or absence of the α-Gal A results in progressive accumulation of globotriaosylceramide Patrícia Varela and Gerson Carvalho contributed equally to this work. * João Bosco Pesquero [email protected] 1
Center for Research and Molecular Diagnostic of Genetic Diseases – Department of Biophysics, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669 - 9o andar, São Paulo 04039-032, Brazil
2
Medical Genetics Unit, Hospital de Apoio de Brasília, Brasília, DF, Brazil
3
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
(Gb3) and other sphingolipids in the lysosomes, mainly in kidney, skin, eyes, heart, and brain (Oliveira and Ferreira 2019). The GLA gene
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