VI. Identification and clinical characterization of alpha-Galactosidase A -10T allele carriers and functional analysis of the C-10T promoter site

Background Fabry disease (FD) is a globotriaosylceramide (Gb3)-triggered multisystemic disorder. The diagnosis is based on low enzymatic galactosidase A (GLA) activity and the identification of GLA variants within the coding region. Patients suffering from Fabry-typical manifestations without variants in the coding region are not routinely treated with enzyme replacement therapy (ERT). In our Interdisciplinary Fabry Center in Münster (IFAZ), we identified patients with Fabry-typical neurological manifestations carrying the GLA mutation -10C>T (rs2071225), but no coding variant.  Current work program  The aim of this applied project is the identification and clinical characterization of additional minor -10T allele carriers with typical FD manifestations but without coding variant. An additional focus will be a screening of patients with small fiber neuropathy (SFN) of unknown etiology.  The current work program includes: 1. Identification and clinical characterization of GLA -10T allele carriers in two patient cohorts: a) patients with typical FD manifestations/symptoms but without coding GLA variants and b) patients with SFN of unknown etiology by sequencing of patients’ DNA. The following clinical parameters will be assessed: 1. clinical events (stroke or transient ischemic attack, myocardial infarction, kidney disease), 2. organ function and structure, and 3. Fabry-related symptoms. 2. Functional studies of the C-10T variation to a) analyze the impact of this variation on GLA expression and transcript- and protein-stability  and b) identify nuclear factors responsible for GLA gene regulation being involved in DNA-protein or protein-protein interactions, which could indirectly result in FD manifestations. 3. Clinical yearly follow-ups and evaluation of the development and progression of FD in -10T allele carriers with FD-specific symptoms.  Expected results  The decreased GLA expression may translate into a reduced level of GLA protein and thus GLA activity in cells of affected organs, indicating that -10C>T is the first non-coding mutation in the regulatory region, which is pathophysiologically relevant and thereby causal for FD.  Univ.-Prof. Dr. Dr. med. E. Brand, Dr. rer. nat. M. Lenders, Dipl.-Biol. M. Schelleckes  Support: Shire International GmbH, 08/2013 – 09/2015