Faculty Collaboration Database

Identification of novel mutations in the α-galactosidase A gene in patients with Fabry disease: pitfalls of mutation analyses in patients with low α-galactosidase A activity. J Cardiol 2011 May;57(3):345-53

Date

02/22/2011

Pubmed ID

21333496

DOI

10.1016/j.jjcc.2010.12.004

Scopus ID

2-s2.0-79955000143 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A (GLA) gene, and the disease is a relatively prevalent cause of left ventricular hypertrophy followed by conduction abnormalities and arrhythmias. Mutation analysis of the GLA gene is a valuable tool for accurate diagnosis of affected families. In this study, we carried out molecular studies of 10 unrelated families diagnosed with Fabry disease.

MATERIALS AND METHODS: Genetic analysis of the GLA gene using conventional genomic sequencing was performed in 9 hemizygous males and 6 heterozygous females. In patients with no mutations in coding DNA sequence, multiplex ligation-dependent probe amplification (MLPA) and/or cDNA sequencing were performed.

RESULTS: We identified a novel exon 2 deletion (IVS1_IVS2) in a heterozygous female by MLPA, which was undetectable by conventional sequencing methods. In addition, the g.9331G>A mutation that has previously been found only in patients with cardiac Fabry disease was found in 3 unrelated, newly-diagnosed, cardiac Fabry patients by sequencing GLA genomic DNA and cDNA. Two other novel mutations, g.8319A>G and 832delA were also found in addition to 4 previously reported mutations (R112C, C142Y, M296I, and G373D) in 6 other families.

CONCLUSIONS: We could identify GLA gene mutations in all hemizygotes and heterozygotes from 10 families with Fabry disease. Mutations in 4 out of 10 families could not be identified by classical genomic analysis, which focuses on exons and the flanking region. Instead, these data suggest that MLPA analysis and cDNA sequence should be considered in genetic testing surveys of patients with Fabry disease.

Author List

Yoshimitsu M, Higuchi K, Miyata M, Devine S, Mattman A, Sirrs S, Medin JA, Tei C, Takenaka T

Author

Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Cardiomyopathy, Hypertrophic, Familial
DNA, Complementary
Fabry Disease
Female
Heterozygote
Humans
Male
Middle Aged
Mutation
Nucleic Acid Amplification Techniques
RNA
Sequence Analysis, DNA
alpha-Galactosidase