TY - JOUR
T1 - Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity
AU - Hammer, Monia B.
AU - Eleuch-Fayache, Ghada
AU - Schottlaender, Lucia V.
AU - Nehdi, Houda
AU - Gibbs, J. Raphael
AU - Arepalli, Sampath K.
AU - Chong, Sean B.
AU - Hernandez, Dena G.
AU - Sailer, Anna
AU - Liu, Guoxiang
AU - Mistry, Pramod K.
AU - Cai, Huaibin
AU - Shrader, Ginamarie
AU - Sassi, Celeste
AU - Bouhlal, Yosr
AU - Houlden, Henry
AU - Hentati, Fayçal
AU - Amouri, Rim
AU - Singleton, Andrew B.
N1 - Funding Information:
The authors thank J. Hammer for his contribution in the correction of the manuscript and his help with the figures. We also thank the affected individuals and their families for taking part in this work. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the Department of Health and Human Services (project number ZIA AG000958-09) and the National Ataxia Foundation. We are also grateful to the Medical Research Council (MRC), the Brain Research Trust, and NORD for funding to H.H., L.V.S., and A.S. and also the MRC/Wellcome Trust Parkinson’s disease consortium grant and the UCLH/UCL Department of Health’s NIHR Biomedical Research Centres funding scheme.
PY - 2013/2/7
Y1 - 2013/2/7
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2012.12.012
DO - 10.1016/j.ajhg.2012.12.012
M3 - Article
C2 - 23332917
AN - SCOPUS:84873733145
SN - 0002-9297
VL - 92
SP - 245
EP - 251
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -