title: Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity.
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.
authors: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Monia B
authors: MB
authors: Hammer
authors: Ghada
authors: G
authors: Eleuch-Fayache
authors: Lucia V
authors: LV
authors: Schottlaender
authors: Houda
authors: H
authors: Nehdi
authors: J Raphael
authors: JR
authors: Gibbs
authors: Sampath K
authors: SK
authors: Arepalli
authors: Sean B
authors: SB
authors: Chong
authors: Dena G
authors: DG
authors: Hernandez
authors: Anna
authors: A
authors: Sailer
authors: Guoxiang
authors: G
authors: Liu
authors: Pramod K
authors: PK
authors: Mistry
authors: Huaibin
authors: H
authors: Cai
authors: Ginamarie
authors: G
authors: Shrader
authors: Celeste
authors: C
authors: Sassi
authors: Yosr
authors: Y
authors: Bouhlal
authors: Henry
authors: H
authors: Houlden
authors: Fayçal
authors: F
authors: Hentati
authors: Rim
authors: R
authors: Amouri
authors: Andrew B
authors: AB
authors: Singleton
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000150:complications* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D005962:Glucosylceramidase; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009128:Muscle Spasticity / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D014416:Tunisia; D001617:beta-Glucosidase / Q000737:chemistry / Q000235:genetics*
chemical_list: D001617:beta-Glucosidase; C517537:GBA2 protein, human; D005962:Glucosylceramidase