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

Barbara Tappino (1) , Roberta Biancheri (2) , Matthew Mort (3) , Stefano Regis (1) , Fabio Corsolini (1) , Andrea Rossi (4) , Marina Stroppiano (5) , Susanna Lualdi (1) , Agata Fiumara (6) , Bruno Bembi (7) , Maja Di Rocco (8) , David N. Cooper (9) , Mirella Filocamo (10)

1 Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche
2 UO Neuropsichiatria
3 Cardiff University
4 Servizio di Neuroradiologia Pediatrica
5 Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche
6 Centro Regionale "Errori Congeniti del Metabolismo
7 Coordinator Centre for Rare Diseases
8 U.O. Pediatria II
9 Institute of Medical Genetics, College of Medicine
10 Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche

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

Mots clés: Life Sciences

Barbara Tappino, Roberta Biancheri, Matthew Mort, Stefano Regis, Fabio Corsolini, et al.. Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. Human Mutation, 2010, 31 (12), ⟨10.1002/humu.21367⟩. ⟨hal-00613758⟩