1. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.
- Author
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Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, and Singleton AB
- Subjects
- Adolescent, Adult, Amino Acid Sequence, Base Sequence, Child, Child, Preschool, DNA Mutational Analysis, Family, Female, Glucosylceramidase, Humans, Male, Molecular Sequence Data, Pedigree, Tunisia, beta-Glucosidase chemistry, Cerebellar Ataxia complications, Cerebellar Ataxia genetics, Genes, Recessive genetics, Muscle Spasticity complications, Muscle Spasticity genetics, Mutation genetics, beta-Glucosidase genetics
- Abstract
Autosomal-recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders with more than 20 different forms currently recognized, many of which are also associated with increased tone and some of which have limb spasticity. Gaucher disease is a lysosomal storage disease resulting from a defect in the enzyme acid β-glucosidase 1. β-glucosidase 2 is an enzyme with similar glucosylceramidase activity but to date has not been associated with a monogenic disorder. We studied four unrelated consanguineous families of Tunisian decent diagnosed with cerebellar ataxia of unknown origin. We performed homozygosity mapping and whole-exome sequencing in an attempt to identify the genetic origin of their disorder. We were able to identify mutations responsible for autosomal-recessive ataxia in these families within the gene encoding β-glucosidase 2, GBA2. Two nonsense mutations (c.363C>A [p.Tyr121(∗)] and c.1018C>T [p.Arg340(∗)]) and a substitution (c.2618G>A [p.Arg873His]) were identified, probably resulting in nonfunctional enzyme. This study suggests GBA2 mutations are a cause of recessive spastic ataxia and responsible for a form of glucosylceramide storage disease in humans., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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