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Functional and biological studies of α-galactosidase A variants with uncertain significance from newborn screening in Taiwan
- Source :
- Molecular Genetics and Metabolism. 123:140-147
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Fabry disease is an X-linked disorder resulted from deficiency of α-galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis. The enzyme activity of dried blood spots and plasma metabolite lyso-Gb3 level from subjects with the variants were measured. Additionally, clinical manifestations were evaluated extensively from the subjects and their relatives. Our results revealed that p.G104V, p.I232T, p.D322H, and p.G360C all exhibited relatively low residual enzyme activities and elevated plasma lyso-Gb3 level. These data strongly suggest that these Fabry mutations may cause classical or later-onset phenotypes. In contrast, neither significantly clinical symptoms nor elevated lyso-Gb3 level was found in cases with p.P60S, p.A108T, p.S304T, p.R356Q, and p.P362T variants, which may be non-pathogenic or milder forms of Fabry variants. More data need to be included for the patients with p.N53D, p.P210S, p.M296L, and p.K391T variants. The established system provides us more information to classify these GLA variants.
- Subjects :
- Male
0301 basic medicine
Endocrinology, Diabetes and Metabolism
Metabolite
In silico
Taiwan
Mutagenesis (molecular biology technique)
Biology
Biochemistry
Pathogenesis
03 medical and health sciences
chemistry.chemical_compound
Neonatal Screening
Endocrinology
Genetics
medicine
Humans
Molecular Biology
Blood Specimen Collection
Newborn screening
Infant, Newborn
medicine.disease
Phenotype
Fabry disease
In vitro
030104 developmental biology
chemistry
alpha-Galactosidase
Mutation
Fabry Disease
Biological Assay
Female
Dried Blood Spot Testing
Biomarkers
Subjects
Details
- ISSN :
- 10967192
- Volume :
- 123
- Database :
- OpenAIRE
- Journal :
- Molecular Genetics and Metabolism
- Accession number :
- edsair.doi.dedup.....c58bdb7dcad1401e49c3a73f8c269644