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Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease.
Front Genet 2019; 10:783FG

Abstract

Fabry disease (FD) is a rare and underdiagnosed X-linked disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A, which leads to storage of complex glycosphingolipids inside of lysosomes in critical organs and tissues, impairing their functions and consequently resulting in a progressive multisystem disease. FD is caused by mutations in the GLA gene, and only 4.6% of described mutations are located in the splice site regions. RNA splicing is an essential step to the formation of functional proteins, and mutations in splice site regions can cause formation of aberrant transcripts leading to disease. Here we report a novel GLA insertion at position c.801+3 in intron 5 (c.801+2_801+3insT) in a Brazilian family with suspicion of FD. The index case, a 46-year-old male, presented undetectable α-galactosidase A activity. Analysis of blood cDNA found two aberrant GLA transcripts. In the first transcript, a novel donor splice site was created promoting formation of an intron inclusion with 37 bp. The splice site was not recognized in the second transcript and the intron 5 was not excised. The wild-type transcript was not formed and both aberrant transcripts lead to a premature stop codon. Despite not being in the canonical site, this new mutation disrupts existing 5' splice site and produces two aberrant transcripts leading to FD.

Authors+Show Affiliations

Center for Research and Molecular Diagnostic of Genetic Diseases - Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil.Department of Nephrology URONEFRO - Hemodiálise e Especialidades, Belém, Brazil.Center for Research and Molecular Diagnostic of Genetic Diseases - Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil.

Pub Type(s)

Case Reports

Language

eng

PubMed ID

31611903

Citation

Varela, Patrícia, et al. "Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease." Frontiers in Genetics, vol. 10, 2019, p. 783.
Varela P, Caldas MM, Pesquero JB. Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease. Front Genet. 2019;10:783.
Varela, P., Caldas, M. M., & Pesquero, J. B. (2019). Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease. Frontiers in Genetics, 10, p. 783. doi:10.3389/fgene.2019.00783.
Varela P, Caldas MM, Pesquero JB. Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease. Front Genet. 2019;10:783. PubMed PMID: 31611903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease. AU - Varela,Patrícia, AU - Caldas,Myrtes Martins, AU - Pesquero,João Bosco, Y1 - 2019/09/27/ PY - 2019/05/10/received PY - 2019/07/24/accepted PY - 2019/10/16/entrez PY - 2019/10/16/pubmed PY - 2019/10/16/medline KW - Fabry disease KW - GLA gene KW - intron inclusion KW - splice site mutation KW - α-galactosidase A SP - 783 EP - 783 JF - Frontiers in genetics JO - Front Genet VL - 10 N2 - Fabry disease (FD) is a rare and underdiagnosed X-linked disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A, which leads to storage of complex glycosphingolipids inside of lysosomes in critical organs and tissues, impairing their functions and consequently resulting in a progressive multisystem disease. FD is caused by mutations in the GLA gene, and only 4.6% of described mutations are located in the splice site regions. RNA splicing is an essential step to the formation of functional proteins, and mutations in splice site regions can cause formation of aberrant transcripts leading to disease. Here we report a novel GLA insertion at position c.801+3 in intron 5 (c.801+2_801+3insT) in a Brazilian family with suspicion of FD. The index case, a 46-year-old male, presented undetectable α-galactosidase A activity. Analysis of blood cDNA found two aberrant GLA transcripts. In the first transcript, a novel donor splice site was created promoting formation of an intron inclusion with 37 bp. The splice site was not recognized in the second transcript and the intron 5 was not excised. The wild-type transcript was not formed and both aberrant transcripts lead to a premature stop codon. Despite not being in the canonical site, this new mutation disrupts existing 5' splice site and produces two aberrant transcripts leading to FD. SN - 1664-8021 UR - https://www.unboundmedicine.com/medline/citation/31611903/Novel_GLA_Mutation_Promotes_Intron_Inclusion_Leading_to_Fabry_Disease L2 - https://doi.org/10.3389/fgene.2019.00783 DB - PRIME DP - Unbound Medicine ER -