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Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease

Tappino, Barbara, Biancheri, Roberta, Mort, Matthew Edwin, Regis, Stefano, Corsolini, Fabio, Rossi, Andrea, Stroppiano, Marina, Lualdi, Susanna, Fiumara, Agata, Bembi, Bruno, Di Rocco, Maja, Cooper, David Neil and Filocamo, Mirella 2010. Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. Human Mutation 31 (12) , E1894-E1914. 10.1002/humu.21367

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Abstract

The characterization of the underlying GALC gene lesions was performed in 30 unrelated patients affected by Krabbe disease, an autosomal recessive leukodystrophy caused by the deficiency of lysosomal enzyme galactocerebrosidase. The GALC mutational spectrum comprised 33 distinct mutant (including 15 previously unreported) alleles. With the exception of 4 novel missense mutations that replaced evolutionarily highly conserved residues (p.P318R, p.G323R, p.I384T, p.Y490N), most of the newly described lesions altered mRNA processing. These included 7 frameshift mutations (c.61delG, c.408delA, c.521delA, c.1171_1175delCATTCinsA, c.1405_1407delCTCinsT, c.302_308dupAAATAGG, c.1819_1826dupGTTACAGG), 3 nonsense mutations (p.R69X, p.K88X, p.R127X) one of which (p.K88X) mediated the skipping of exon 2, and a splicing mutation (c.1489+1G>A) which induced the partial skipping of exon 13. In addition, 6 previously unreported GALC polymorphisms were identified. The functional significance of the novel GALC missense mutations and polymorphisms was investigated using the MutPred analysis tool. This study, reporting one of the largest genotype-phenotype analyses of the GALC gene so far performed in a European Krabbe disease cohort, revealed that the Italian GALC mutational profile differs significantly from other populations of European origin. This is due in part to a GALC missense substitution (p.G553R) that occurs at high frequency on a common founder haplotype background in patients originating from the Naples region.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords: GALC mutations ; Krabbe disease ; Leukodystrophy ; Genotype-Phenotype analysis ; Founder mutation
Additional Information: Mutation in Brief
Publisher: Wiley Blackwell
ISSN: 1059-7794
Last Modified: 07 Apr 2019 00:18
URI: http://orca.cf.ac.uk/id/eprint/22802

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