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

The characterization of the underlying GALC gene lesions was performed in 30unrelated patients affected by Krabbe disease, an autosomal recessive leukodystrophy caused bythe deficiency of lysosomal enzyme galactocerebrosidase. The GALC mutational spectrumcomprised 33 distinct mutant (including 15 previously unreported) alleles. With the exception of 4novel 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 inducedthe partial skipping of exon 13. In addition, 6 previously unreported GALC polymorphisms wereidentified. The functional significance of the novel GALC missense mutations and polymorphismswas 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 ofEuropean origin. This is due in part to a GALC missense substitution (p.G553R) that occurs at highfrequency on a common founder haplotype background in patients originating from the Naplesregion.