title: Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations.
abstract: Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare.
authors.affiliation: 1] Medical Genetics Center, Cairo, Egypt [2] Children's Hospital, Ain Shams University, Cairo, Egypt.
authors.forename: Solaf M
authors.initials: SM
authors.lastname: Elsayed
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Thoenes
authors.affiliation: Human Genetics and Genome Research Division, Clinical Genetics Department, National Research Centre, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Computational Biology Group, Oxford Gene Technology, Oxford, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Swan
authors.affiliation: 1] Medical Genetics Center, Cairo, Egypt [2] Children's Hospital, Ain Shams University, Cairo, Egypt.
authors.forename: Ezzat
authors.initials: E
authors.lastname: Elsobky
authors.affiliation: Institute for Human Genetics, University of Lübeck, Campus Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Zühlke
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.affiliation: 1] Cologne Center for Genomics and Centre for Molecular Medicine, University of Cologne, Cologne, Germany [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: 1] Cologne Center for Genomics and Centre for Molecular Medicine, University of Cologne, Cologne, Germany [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: 1] Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany [2] Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002648:Child; D018389:Codon, Nonsense; D003241:Consanguinity; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D013049:Spectrin / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000175:diagnosis* / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; C495133:SPTBN2 protein, human; D013049:Spectrin