Intronic mutations in GLA causes Fabry disease (1138.5)

Abstract

INTRODUCTION: Fabry disease (FD) is a rare X‐linked disorder, due to a defect of lysosomal α‐Galactosidase A (GalA), which determines cellular storage of globotryalosil ceramide (Gb3), eventually causing multysistemic dysfunctions. Male patients are diagnosed by enzyme activity assay and female patients by genetic study. AIMS: To characterize molecular defects in a family of patients with unconfirmed diagnosis of FD. PATIENTS & METHODS: Male with impaired GalA activity and his 7 years old daughter, presenting FD symptoms. Patients carry genetic defects in GLA up to date validated as polymorphisms (rs207122, rs2071397). RT‐PCR was performed to asses GLA transcripts levels in patient's derived leukocytes. GalA and Gb3 expression were evaluated by immunofluorescence in daughter's skin biopsy. RESULTS: GLA transcript levels are significantly reduced in both patients. Immunofluorescence of skin biopsy revealed lysosomal inclusions of Gb3 mainly in dermal fibroblasts, while GalA present lower expression, compared to a control biopsy. CONCLUSIONS: The association of the intronic mutations rs207122, rs2071397 affects transcription of GLA and causes Gb3 accumulation, determining FD phenotype.Grant Funding Source: Instituto Carlos III Spain