STUB1 – Spinocerebellar ataxia autosomal recessive 16

STUB1 encodes the C-terminus of Hsc70-interacting protein (CHIP), a chaperone-associated E3 ubiquitin ligase critical for protein quality control. Biallelic loss-of-function variants in STUB1 underlie autosomal recessive spinocerebellar ataxia 16 (SCAR16) (MONDO_0014339), manifesting with early-onset cerebellar ataxia and cognitive impairment.

Multiple unrelated families have been reported with SCAR16 due to recessive STUB1 variants: a consanguineous pedigree with four affected siblings homozygous for c.194A>G (p.Asn65Ser)[PMID:25258038], a separate family with two siblings homozygous for c.737C>T (p.Thr246Met)[PMID:24113144], and an additional individual with compound heterozygous c.82G>A (p.Glu28Lys) and c.430T>A (p.Lys144Ter)[PMID:25258038]. In total, six probands across three pedigrees demonstrate recessive inheritance of STUB1 variants with segregation in affected relatives in each family.

Genetic evidence supports autosomal recessive inheritance with segregation in five additional affected relatives and six probands. Pathogenic variant types include missense substitutions in the TPR and U-box domains and truncating alleles, with no clear founder effect. Key variants: c.194A>G (p.Asn65Ser) in the U-box domain and c.737C>T (p.Thr246Met) disrupting E3 ligase activity.

Functional studies corroborate a loss-of-function mechanism. In vitro assays of six SCAR16-associated missense variants (E28K, N65S, K145Q, M211I, S236T, T246M) reveal impaired CHIP stability, abnormal oligomerization, reduced α-helical content, and altered ubiquitin ligase activity ([PMID:28396517]). A mouse and rat knock-in model of T246M recapitulates motor and cognitive cerebellar dysfunction ([PMID:30222779]).

The convergence of genetic segregation and concordant functional data establishes a strong association between STUB1 loss-of-function and SCAR16. The mechanism involves disruption of CHIP’s E3 ligase activity leading to impaired proteostasis in cerebellar neurons. Additional evidence from cellular rescue and preclinical models further substantiates this link.

Key take-home: Biallelic STUB1 variants cause SCAR16 by loss of CHIP ubiquitin ligase function, supporting clinical testing for STUB1 in early-onset recessive ataxia with cognitive features.

References

• Orphanet journal of rare diseases • 2014 • STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity. PMID:25258038
• Human molecular genetics • 2014 • Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. PMID:24113144
• Bioscience reports • 2017 • In vitro characterization of six STUB1 variants in spinocerebellar ataxia 16 reveals altered structural properties for the encoded CHIP proteins. PMID:28396517
• PLoS genetics • 2018 • Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16. PMID:30222779

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