Dataset Information

Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation.

ABSTRACT:

Objective

To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48.

Methods

We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members.

Results

Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent cognitive decline and behavioral changes. Whole-exome sequencing identified a novel heterozygous frameshift variant c.731_732delGC (p.C244Yfs*24) in STUB1 segregating with the disease. This variant was present in a linkage peak on chromosome 16p13.3. Neuropathologic examination of 3 cases revealed a consistent pattern of ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem. In addition, tau pathology was present in 1 case.

Conclusions

This study confirms previous findings of heterozygous STUB1 mutations as the cause of SCA48 and highlights its prominent cognitive involvement, besides cerebellar ataxia and movement disorders as cardinal features. The presence of intranuclear inclusions is a pathologic hallmark of the disease. Future studies will provide more insight into its pathologic heterogeneity.

SUBMITTER: Mol MO

PROVIDER: S-EPMC7164971 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Clinical and pathologic phenotype of a large family with heterozygous <i>STUB1</i> mutation.

Mol Merel O MO van Rooij Jeroen G J JGJ Brusse Esther E Verkerk Annemieke J M H AJMH Melhem Shamiram S den Dunnen Wilfred F A WFA Rizzu Patrizia P Cupidi Chiara C van Swieten John C JC Donker Kaat Laura L

Neurology. Genetics 20200323 3

<h4>Objective</h4>To describe the clinical and pathologic features of a novel pedigree with heterozygous <i>STUB1</i> mutation causing SCA48.<h4>Methods</h4>We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members.<h4>Results</h4>Patients presented with adult-onset gait disturbance (ataxia or parkinsonism), combined with prominent c ...[more]

PMID: 32337344

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Project description:A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism.With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c.194A?>?G, p.Asn65Ser) that segregated in three affected siblings, and a missense change (c.82G?>?A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A?>?T, p.Lys144Ter) in another patient. STUB1 encodes CHIP (C-terminus of Heat shock protein 70 - Interacting Protein), a dual function protein with a role in ubiquitination as a co-chaperone with heat shock proteins, and as an E3 ligase. We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate. These results are consistent with previous studies highlighting this as a critical residue for the interaction between CHIP and its co-chaperones. Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls.These results suggest that STUB1 mutations might cause disease by impacting not only the E3 ligase function, but also its protein interaction properties and protein amount. Whether the clinical heterogeneity seen in STUB1 ARCA can be related to the location of the mutations remains to be understood, but interestingly, all siblings with the p.Asn65Ser substitution showed a marked appearance of accelerated aging not previously described in STUB1 related ARCA, none display hormonal aberrations/clinical hypogonadism while some affected family members had diabetes, alopecia, uveitis and ulcerative colitis, further refining the spectrum of STUB1 related disease.