Spectrin mutations cause spinocerebellar ataxia type 5

Abstract

We have discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region. Beta-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

Genomic analysis identifies masqueraders of full‐term cerebral palsy

“…Furthermore, case 17 was also a compound heterozygote of SPTBN2 variants. SPTBN2 has been identified in both autosomal dominant and autosomal recessive spinocerebellar ataxia,42 together with CP 34. Although both SPTBN2 variants in case 17 were classified as having uncertain significance and the patient's clinical presentation was consistent with SCN2A ‐related disorder, we cannot eliminate the possibility that those variants in SPTNBN2 could contribute to the patient's phenotype.…”

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…In puratrophin-1 (PRTPHN1/PLEKHG4) for 16q-linked ADCA phenotype and contactin 4 (CNTN4) for SCA16, each published specific single nucleotide polymorphism was analyzed. The PCR mixtures and fragment analyses were basically the same as those reported previously van Swieten et al 2003;Ikeda et al 2006;Miura et al 2006;Yabe et al 2003;Waters et al 2006).…”

Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy

“…Heterozygous mutations in b-III spectrin (SPTBN2) were previously shown to cause spinocerebellar ataxia type-5. 3 It is tempting to speculate that cerebellar atrophy in patients with mutations in SPTAN1 is caused at least in part by the aggregation of b-III spectrin. This is consistent with the fact that b-III, unlike b-II spectrin, is abundantly expressed in the human cerebellum (Allen Brain Atlas; http://human.brain-map.org/).…”

“…1,2 Heterozygous mutations in the b-III subunit (SPTBN2) were shown to cause spinocerebellar ataxia type-5. 3 Recently, de novo in-frame mutations in the a-II spectrin subunit (SPTAN1) were identified in patients with severe intellectual disability (ID), infantile spasms (IS) with hypsarrhythmia, hypomyelination, and atrophy of various regions of the brain, including the cerebellum and brainstem. 4 These mutations are located in a C-terminal domain that includes the nucleation site involved in a/b spectrin heterodimer formation.…”