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.

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

“…The patients in this study showed clear cerebellar atrophy. 11 No cranial MRIs were available for our patients; although cerebellar symptoms do not necessarily correlate with cerebellar atrophy, we assume that they have cerebellar atrophy too.…”

“…We describe a homozygous 5-bp deletion in SPTBN2 in a consanguineous family with infantile ataxia, developmental delay (d) Scheme of SPTBN2 gene structure and deduced protein with locations of the recessive (in red; human mutations described herein and by Lise et al 11 , and the more C-terminal mutation that was recently identified in Beagle dogs) and dominant (SCA5; in blue) mutations. For clarity, the one-letter code was applied for mutation designation in this subset of the figure. and pyramidal signs that was unlinked to the known ARCA loci.…”

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

“…2 For example, some recessive ataxias are not contained in the SCAR or the ARCA list (eg, Friedreich’s ataxia or AOA1), and some recessive ataxias are listed only in one of them (eg, AOA2 only in SCAR classification). Moreover, some dominant ataxias can also be inherited in a recessive manner and vice versa ( GRID2 , 3 AFG3L2 , 4 SPTBN2 5 ), making it difficult to designate them as either on the SCA or the SCAR/ARCA list (or both). Most important, the systematic value of each of these classification systems is also very limited.…”

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

“…AFG3L2 was also recently involved in an AR syndrome comprised of spastic ataxia and neuropathy, SPAX5 [53]. SPTBN2, whose in-frame deletions and missense mutations account for AD-SCA5, was linked to AR ataxia and cognitive impairment, with homozygous loss-of-function mutations [54,55].…”