Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development

Area of Science:

• Neurogenetics
• Molecular Neurology
• Developmental Neuroscience

Background:

• Beta-III spectrin (encoded by SPTBN2) is crucial for cerebellar function.
• Heterozygous SPTBN2 mutations cause Spinocerebellar Ataxia Type 5 (SCA5), a dominant cerebellar ataxia.
• The role of beta-III spectrin in brain development and cognition was previously unknown.

Purpose of the Study:

• To investigate the genetic basis of a recessive ataxia with cognitive impairment.
• To explore the function of beta-III spectrin in cortical development and cognition.
• To characterize a novel spectrin-associated neurological disorder.

Main Methods:

• Targeted capture and next-generation sequencing to identify mutations in SPTBN2.
• Whole-genome sequencing and SNP array analysis to exclude other genetic causes.
• Phenotypic analysis of a beta-III spectrin knockout mouse model.

Main Results:

• A homozygous stop codon in SPTBN2 was identified in a family with recessive ataxia and cognitive impairment.
• Beta-III spectrin knockout mice exhibited prefrontal cortex abnormalities and cognitive deficits.
• These findings implicate beta-III spectrin in cortical development and cognitive function.

Conclusions:

• Cognitive impairment is an integral feature of Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1).
• Beta-III spectrin plays a critical role in both cerebellar function and cortical development/cognition.
• This study defines a new class of neurological disorders, neuronal spectrinopathies, including SCA5 and SPARCA1.