A Family with Spinocerebellar Ataxia Type 5 Found to Have a Novel Missense Mutation within a SPTBN2 Spectrin Repeat

Abstract

OBJECTIVE Identification of a novel missense mutation in the SPTBN2 gene of a family with a clinical diagnosis of spinocerebellar ataxia type 5 (SCA5). METHODS A family with late-onset autosomal dominant pure cerebellar ataxia, consistent with SCA5 but lacking previously reported SPTBN2 mutations, was identified. DNA was collected from seven individuals across two generations and the SPTBN2 gene on chromosome 11 was sequenced. RESULTS A nonsynonymous heterozygous substitution in exon 12 was detected in individuals diagnosed with SCA5 while unaffected family members did not possess this variant. The identified c.1415C>T variant results in a p.T472M substitution in the second SPEC domain of the beta-III spectrin protein. The threonine at position 472 is not in close proximity to the characteristic residues that define the SPEC domain and is variable across diverse SPEC domains, yet is highly conserved in SPTBN2. Consistent with these observations, bioinformatic analysis of the p.T472M variant suggests it to be pathological. CONCLUSION Two deletions within the SPTBN2 SPEC domains (E532_M544del and L629_R634delinsW) have been previously reported to cause SCA5, but this is the first missense mutation in this region of the protein shown to likely be pathogenic.

Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

“…SPTBN2 encodes a b3-spectrin with high expression in Purkinje cells that is involved in excitatory glutamate signaling through stabilization of the glutamate transporter EAAT4 at the membrane's surface. Heterozygous in-frame SPTBN2 mutations cause SCA5, a rare SCA subtype with only five mutations reported, [4][5][6] with the mean age of onset at 33 years and mostly normal lifespan.…”

Mutant -III Spectrin Causes mGluR1 Mislocalization and Functional Deficits in a Mouse Model of Spinocerebellar Ataxia Type 5

“…Rotarod latency was assessed using 6-to 9-week-old, 16-week-old, and 26-week-old mice using an accelerating rotarod apparatus (Ugo Basile EZ-rod; AccuScan) as previously described (Clark et al, 1997). Mice underwent four trials per day for 4 consecutive days, with at least 10 min rest between trials.…”

“…To date, seven distinct SPTBN2 mutations have been reported in families with neurodegenerative disease. Five of these mutations are associated with dominant spinocerebellar ataxia (SCA5) and two mutations are found in patients with more complex recessive disorders involving early onset motor and cognitive deficits (Ranum et al, 1994;Bürk et al, 2004;Ikeda et al, 2006;Lise et al, 2012;Cho and Fogel, 2013;Jacob et al, 2013;Elsayed et al, 2014). In addition to providing insight into SCA5 pathogenesis, identifying how these novel spectrin mutations cause ataxia will broaden our understanding of the role of cytoskeletal proteins in neurologic disease and the molecular pathways leading to neurodegeneration.…”

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia

“…More than 20 genes are known to date (see Table S1). [7][8][9][10][11] The identification of three unrelated Francesco Nicita and Marta Nardella have contributed equally to this work. [3][4][5][6] Heterozygous missense variants of SPTBN2 have been initially associated to autosomal dominant spinocerebellar ataxia 5 (SCA5; MIM#600224) characterized by a slowly progressive cerebellar syndrome with downbeat nystagmus and tremor, beginning in the third decade with a tendency toward anticipation in later generations.…”