Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form.

[krabbe disease]

Krabbe disease is an autosomal recessive leukodystrophy caused by the deficiency of the galactocerebrosidase (GALC ) enzyme . It is pathologically characterized by demyelination of the central and peripheral nervous systems by accumulation of galactosylsphingosine . To date , more than 120 mutations in the GALC gene have been reported worldwide and genotype-phenotype correlations have been reported in some types of mutations . In this study , we analyzed 22 unreported Japanese patients with Krabbe disease and summarized a total of 51 Japanese patients , including 29 previously reported patients . To elucidate how GALC mutations impair enzymatic activity , multiple disease-causing mutations including common mutations and polymorphisms were investigated for enzymatic activity and precursor processing ability with transient expression system . We also performed 3 -D enzyme structure analysis to determine the effect of each new mutation . Five novel mutations were detected including one deletion c .1808 delT [p .L 603 X ], one nonsense mutation c .1023 C >G [p .Y 341 X ], and three missense mutations c .209 T >C [p .L 70 P ], c .1054 G >A [p .G 352 R ], and c .1937 G >C [p .G 646 A ]. For the total of 51 patients , 59 % had late-onset forms of Krabbe disease . Seven common mutations accounted for 58 % of mutant alleles of patients with Krabbe disease in Japan . Infantile -onset mutations had almost no enzyme activity , while late-onset mutations had 4 %-20 % of normal enzyme activity . The processing rate of precursor GALC protein to mature form was slower for infantile -onset mutations . Heat stability of the mutant proteins revealed that p .G 270 D was more stable compared to the other mutations . The constructed 3 D-model showed that the residues for Krabbe mutations were less solvent-accessible and located in the core region of GALC protein . In conclusion , we have demonstrated that the most common phenotype in Japan is the late-onset type , that the enzyme activity for GALC mutants is correlated with mutational severity , and that the most pathogenic factor is due to the processing rate from the precursor to the mature protein .

Diseases
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Diseases presenting "polymorphisms were investigated for enzymatic activity and precursor processing ability with transient expression system" symptom

krabbe disease

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