A Novel GBA2 Gene Missense Mutation in Spastic Ataxia

Autosomal recessive cerebellar ataxias (ARCA) encompass a heterogeneous group of rare diseases that affect the cerebellum, the spinocerebellar tract and/or the sensory tracts of the spinal cord. We investigated a consanguineous Cypriot family with spastic ataxia, aiming towards identification of the causative mutation. Family members were clinically evaluated and studied at the genetic level. Linkage analysis at marker loci spanning known ARCA genes/loci revealed linkage to the APTX locus. Thorough investigation of the APTX gene excluded any possible mutation. Whole genome linkage screening using microsatellite markers and whole genome SNP homozygosity mapping using the Affymetrix Genome‐Wide Human SNP Array 6.0 enabled mapping of the disease gene/mutation in this family to Chromosome 9p21.1‐p13.2. Due to the large number of candidate genes within this region, whole‐exome sequencing of the proband was performed and further analysis of the obtained data focused on the mapped interval. Further investigation of the candidate variants resulted in the identification of a novel missense mutation in the GBA2 gene. GBA2 mutations have recently been associated with hereditary spastic paraplegia and ARCA with spasticity. We hereby report a novel GBA2 mutation associated with spastic ataxia and suggest that GBA2 mutations may be a relatively frequent cause of ARCA.

[1]  Ellen Sidransky,et al.  The link between the GBA gene and parkinsonism , 2012, The Lancet Neurology.

[2]  S. Tsuji,et al.  A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease. , 1987, The New England journal of medicine.

[3]  R. Hammer,et al.  Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. , 2006, The Journal of clinical investigation.

[4]  M. Horowitz,et al.  Acid beta-glucosidase: enzymology and molecular biology of Gaucher disease. , 1990, Critical reviews in biochemistry and molecular biology.

[5]  H. Morita,et al.  Exome sequencing reveals a homozygous SYT14 mutation in adult-onset, autosomal-recessive spinocerebellar ataxia with psychomotor retardation. , 2011, American journal of human genetics.

[6]  Pask Ea,et al.  HOMOSEXUALITY AS A CRIME. , 1965 .

[7]  A. Harding CLASSIFICATION OF THE HEREDITARY ATAXIAS AND PARAPLEGIAS , 1983, The Lancet.

[8]  C. Espinós,et al.  Orphanet Journal of Rare Diseases BioMed Central Review , 2006 .

[9]  S. Chamberlain,et al.  FRIEDREICH'S ATAXIA IN KATHIKAS-ARODHES, CYPRUS , 1988, The Lancet.

[10]  Janna H. Neltner,et al.  GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology , 2012, Neurology.

[11]  K. Kleopa,et al.  Investigation of SCA10 in the Cypriot population: Further exclusion of SCA dynamic repeat mutations , 2012, Journal of the Neurological Sciences.

[12]  Henry Houlden,et al.  Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. , 2013, American journal of human genetics.

[13]  H. Kremer,et al.  Reviewing the genetic causes of spastic-ataxias , 2012, Neurology.

[14]  L. Middleton,et al.  A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia , 2008, BMC Medical Genetics.

[15]  K. Christodoulou,et al.  High frequency of Friedreich's ataxia carriers in the Paphos district of Cyprus. , 2009, Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology.

[16]  M. Horowitz,et al.  Acid β-Glucosidase: Enzymology and Molecular Biology of Gaucher Diseas , 1990 .

[17]  M. Koenig,et al.  Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. , 2001, American journal of human genetics.

[18]  S. Matern,et al.  Purification and Characterization of a Microsomal Bile Acid β-Glucosidase from Human Liver* , 1997, The Journal of Biological Chemistry.

[19]  F. Lottspeich,et al.  Molecular cloning and expression of human bile acid beta-glucosidase. , 2001, The Journal of biological chemistry.

[20]  Alexandra Durr,et al.  Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. , 2013, American journal of human genetics.

[21]  J. Ott,et al.  Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. , 1985, American journal of human genetics.

[22]  J. Weber,et al.  Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p. , 1995, Human molecular genetics.

[23]  P. Martinez-Martinez,et al.  Ceramide function in the brain: when a slight tilt is enough , 2012, Cellular and Molecular Life Sciences.

[24]  N. Drouot,et al.  Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management , 2010, neurogenetics.

[25]  B. Castellotti,et al.  Ataxia With Oculomotor Apraxia Type 1 (AOA1): Clinical and Neuropsychological Features in 2 New Patients and Differential Diagnosis , 2008, Journal of child neurology.

[26]  W. Bönigk,et al.  The Non-lysosomal β-Glucosidase GBA2 Is a Non-integral Membrane-associated Protein at the Endoplasmic Reticulum (ER) and Golgi* , 2012, The Journal of Biological Chemistry.

[27]  Peter Nürnberg,et al.  HomozygosityMapper—an interactive approach to homozygosity mapping , 2009, Nucleic Acids Res..