Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity

Monia B. Hammer, Ghada Eleuch-Fayache, Lucia V. Schottlaender, Houda Nehdi, J. Raphael Gibbs, Sampath K. Arepalli, Sean B. Chong, Dena G. Hernandez, Anna Sailer, Guoxiang Liu, Pramod K. Mistry, Huaibin Cai, Ginamarie Shrader, Celeste Sassi, Yosr Bouhlal, Henry Houlden, Fayçal Hentati, Rim Amouri, Andrew B. Singleton

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)245-251
Number of pages7
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 7 2013
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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