1. Mutations in GBA2 Cause Autosomal-Recessive Cerebellar Ataxia with Spasticity
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Henry Houlden, Monia B. Hammer, Rim Amouri, A Sailer, Sean B. Chong, J. Raphael Gibbs, Huaibin Cai, Houda Nehdi, Lucia Schottlaender, Celeste Sassi, Yosr Bouhlal, Pramod K. Mistry, Sampath Arepalli, Ghada Eleuch-Fayache, Ginamarie Shrader, Guoxiang Liu, Andrew B. Singleton, Dena G. Hernandez, and Fayçal Hentati
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Adult ,Male ,Tunisia ,Ataxia ,Adolescent ,Cerebellar Ataxia ,DNA Mutational Analysis ,Molecular Sequence Data ,Nonsense mutation ,Genes, Recessive ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Report ,Genetics ,medicine ,Lysosomal storage disease ,Humans ,Family ,Genetics(clinical) ,Amino Acid Sequence ,Child ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Mutation ,Base Sequence ,Cerebellar ataxia ,beta-Glucosidase ,Glucosylceramidase activity ,Autosomal recessive cerebellar ataxia ,Disease gene identification ,medicine.disease ,Pedigree ,3. Good health ,Muscle Spasticity ,Child, Preschool ,Glucosylceramidase ,Female ,medicine.symptom ,030217 neurology & neurosurgery - 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.363CA [p.Tyr121(∗)] and c.1018CT [p.Arg340(∗)]) and a substitution (c.2618GA [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.
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