title: A novel GBA2 gene missense mutation in spastic ataxia.
abstract: 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.
authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Christina
authors.initials: C
authors.lastname: Votsi
authors.forename: Eleni
authors.initials: E
authors.lastname: Zamba-Papanicolaou
authors.forename: Lefkos T
authors.initials: LT
authors.lastname: Middleton
authors.forename: Marios
authors.initials: M
authors.lastname: Pantzaris
authors.forename: Kyproula
authors.initials: K
authors.lastname: Christodoulou
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002524:Cerebellar Ataxia / Q000235:genetics; D002874:Chromosome Mapping; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D056426:Genetic Loci; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D005962:Glucosylceramidase; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D009128:Muscle Spasticity / Q000235:genetics*; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000235:genetics*; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D055815:Young Adult; D001617:beta-Glucosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D005819:Genetic Markers; D001617:beta-Glucosidase; C517537:GBA2 protein, human; D005962:Glucosylceramidase
keywords: Spastic ataxia; exome sequencing; homozygosity mapping; recessive ataxia