Author(s): Ribeiro, Diogo ; Duarte, Ana Joana ; Amaral, Olga
Date: 2021
Persistent ID: http://hdl.handle.net/10400.18/8127
Origin: Repositório Científico do Instituto Nacional de Saúde
Subject(s): Lysosomal Storage Disease; LSDs; Tay Sachs; Fabry; iPSCs; CRISPR based gene editing; Human Genetics; Doenças Genéticas; Portugal
Fabry Disease (FD, MIM#301500) and Tay Sachs disease (TSD, MIM #272800) are two sphingolipidoses that belong to the vast group of lysosomal storage disorders (LSDs). These diseases are characterized by mutations in genes that encode lysosomal hydrolases or activator proteins engaged in the intralysosomal degradation of sphingolipids. In the Portuguese population, LSDs have a prevalence of 1/5000 live births. FD and TSD variant B1 are two of the most prevalent sphingolipidoses in the Portuguese population. FD is multisystemic and is caused by mutations on the GLA gene (MIM #300644) leading to alpha-galactosidase A impairment and major accumulation of globotriaosylceramide (Gb3) in the lysosomes. TSD variant B1 is a neurodegenerative LSD that, although rare, is the most frequent form of TSD in North of Portugal. The TSD variant B1, with mutation p.R178H (rs28941770), is frequent in specific population groups of Iberian heritage. The p.R178H HEXA (MIM#606869.0006) mutation has a carrier frequency of 1:340 in the Portuguese population and 1:119 in the North of Portugal. In our group, we are attempting to use gene editing through CRISPR/Cas9 as a therapeutic tool to correct the p.W287X (rs104894839) FD mutation and the p.R178H TSD variant B1 mutation. For this purpose, we first generate, using non-integrative epissomal vectors, two induced pluripotent stem cells (iPSCs) lines derived from skin fibroblasts of FD patient (INSAi002-A) and TSD variant B1 patient (in progress). As a near future perspective, we will use CRISPR/Cas9 technology to correct these mutations
