title: Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development.
abstract: β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as "Lincoln ataxia," because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lise
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Clarkson
authors.forename: Emma
authors.initials: E
authors.lastname: Perkins
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kwasniewska
authors.forename: Elham
authors.initials: E
authors.lastname: Sadighi Akha
authors.forename: Ricardo Parolin
authors.initials: RP
authors.lastname: Schnekenberg
authors.forename: Daumante
authors.initials: D
authors.lastname: Suminaite
authors.forename: Jilly
authors.initials: J
authors.lastname: Hope
authors.forename: Ian
authors.initials: I
authors.lastname: Baker
authors.forename: Lorna
authors.initials: L
authors.lastname: Gregory
authors.forename: Angie
authors.initials: A
authors.lastname: Green
authors.forename: Chris
authors.initials: C
authors.lastname: Allan
authors.forename: Sarah
authors.initials: S
authors.lastname: Lamble
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jayawant
authors.forename: Gerardine
authors.initials: G
authors.lastname: Quaghebeur
authors.forename: M Zameel
authors.initials: MZ
authors.lastname: Cader
authors.forename: Sarah
authors.initials: S
authors.lastname: Hughes
authors.forename: Richard J E
authors.initials: RJ
authors.lastname: Armstrong
authors.forename: Alexander
authors.initials: A
authors.lastname: Kanapin
authors.forename: Andrew
authors.initials: A
authors.lastname: Rimmer
authors.forename: Gerton
authors.initials: G
authors.lastname: Lunter
authors.forename: Iain
authors.initials: I
authors.lastname: Mathieson
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: David
authors.initials: D
authors.lastname: Buck
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Taylor
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Gilean
authors.initials: G
authors.lastname: McVean
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Samantha J L
authors.initials: SJ
authors.lastname: Knight
authors.forename: Mandy
authors.initials: M
authors.lastname: Jackson
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Németh
mesh_terms: D000328:Adult; D000818:Animals; D002531:Cerebellum / Q000254:growth & development / Q000473:pathology; D002874:Chromosome Mapping; D003072:Cognition Disorders / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology; D013049:Spectrin / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000503:physiopathology
chemical_list: C495133:SPTBN2 protein, human; D013049:Spectrin