Globoid cell leukodystrophy is an autosomal recessive inherited disease caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Although the severe, rapidly progressing infantile form is the most common, late-onset forms have been described. We investigated the molecular basis of GALC deficiency in a patient with a late-life mild form of globoid cell leukodystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genotype was reconstructed by analyzing this gene in her six obligate carrier offspring. One allele contained the mutation 809G>A (G270D) in the 1637C background, while the other allele contained three sequence variants: 1609G>A (G537R), 1873G>A (A625T), and 1650T>A (V550V) in the 1637T background. These mutations were confirmed in the proband's genomic DNA isolated from a sural nerve biopsy. Expression studies indicated that the G537R is a disease-causing mutation, as it resulted in no GALC activity, either alone or together with the A625T. This A625T sequence variant did not affect the enzyme activity, at least when expressed in the 1637T background. The mild clinical phenotype was likely to be associated with the 809G>A, since residual GALC activity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other patients with late-onset GLD.

DE GASPERI, R., GAMA SOSA, M.a., Sartorato, E., Battistini, S., Raghavan, S., & Kolodny, E.h. (1999). Molecular basis of late-life globoid cell leukodystrophy. HUMAN MUTATION, 14, 256-262.

Molecular basis of late-life globoid cell leukodystrophy.

BATTISTINI, STEFANIA;
1999

Abstract

Globoid cell leukodystrophy is an autosomal recessive inherited disease caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Although the severe, rapidly progressing infantile form is the most common, late-onset forms have been described. We investigated the molecular basis of GALC deficiency in a patient with a late-life mild form of globoid cell leukodystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genotype was reconstructed by analyzing this gene in her six obligate carrier offspring. One allele contained the mutation 809G>A (G270D) in the 1637C background, while the other allele contained three sequence variants: 1609G>A (G537R), 1873G>A (A625T), and 1650T>A (V550V) in the 1637T background. These mutations were confirmed in the proband's genomic DNA isolated from a sural nerve biopsy. Expression studies indicated that the G537R is a disease-causing mutation, as it resulted in no GALC activity, either alone or together with the A625T. This A625T sequence variant did not affect the enzyme activity, at least when expressed in the 1637T background. The mild clinical phenotype was likely to be associated with the 809G>A, since residual GALC activity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other patients with late-onset GLD.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/40541
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