ArticleOrphanet journal of rare diseases2017
STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.
Article in Orphanet journal of rare diseases, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 66 citations in OpenAlex.
- Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis.bioRxiv : the preprint server for biology · 2026Article
- Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.Cerebellum (London, England) · 2026Review
- A novel STUB1 p.(Gln118*) nonsense variant in compound heterozygosity causes autosomal recessive spinocerebellar ataxia type 16 in a Chinese patient.BMC neurology · 2026Article
- Review
- NovelJCEM case reports · 2026Article
- CHIP and aging: a key regulator of proteostasis and cellular senescence.Biogerontology · 2025Review
- Clinical and functional characterization of a novel STUB1 mutation in a Chinese spinocerebellar ataxia 48 pedigree.Orphanet journal of rare diseases · 2024Article
- Article
- Article
- The E3 ubiquitin ligase RNF216/TRIAD3 is a key coordinator of the hypothalamic-pituitary-gonadal axis.iScience · 2022Article
- Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome.Journal of molecular neuroscience : MN · 2022Article
- A de novo STUB1 variant associated with an early adult-onset multisystemic ataxia phenotype.Journal of neurology · 2021Article
- Movement Disorders Associated with Hypogonadism.Movement disorders clinical practice · 2021Review
- Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- Correspondence on "Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment" by Roux et al.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.Journal of neurology · 2021Article
- Tripartite motif-containing protein 6 facilitates growth and migration of breast cancer through degradation of STUB1.European journal of histochemistry : EJH · 2021Article
- It's not just a phase; ubiquitination in cytosolic protein quality control.Biochemical Society transactions · 2021Review
- C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.Current neuropharmacology · 2021Review
- Mutations in Hsp90 Cochaperones Result in a Wide Variety of Human Disorders.Frontiers in molecular biosciences · 2021Review
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11 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundCHIP, the protein encoded by STUB1, is a central component of cellular protein homeostasis and interacts with several key proteins involved in the pathogenesis of manifold neurodegenerative diseases. This gives rise to the hypothesis that mutations in STUB1 might cause a far more multisystemic neurodegenerative phenotype than the previously reported cerebellar ataxia syndrome.
methodsWhole exome sequencing data-sets from n = 87 index subjects of two ataxia cohorts were screened for individuals with STUB1 mutations. In-depth phenotyping by clinical evaluation and neuroimaging was performed in mutation carriers.
resultsWe identified four novel STUB1 mutations in three affected subjects from two index families (frequency 2/87 = 2.3%). All three subjects presented with a severe multisystemic phenotype including severe dementia, spastic tetraparesis, epilepsy, and autonomic dysfunction in addition to cerebellar ataxia, plus hypogonadism in one index patient. Diffusion tensor imaging revealed degeneration of manifold supra- and infratentorial tracts.
conclusionsOur findings provide clinical and imaging support for the notion that CHIP is a crucial converging point of manifold neurodegenerative processes, corresponding with its universal biological function in neurodegeneration. Further, our data reveal the second STUB1 family with ataxia plus hypogonadism reported so far, demonstrating that Gordon Holmes syndrome is indeed a recurrent manifestation of STUB1. However, it does not present in isolation, but as part of a broad multisystemic neurodegenerative process. This supports the notion that STUB1 disease should be conceptualized not by historical or clinical syndromic names, but as a variable multisystemic disease defined by disturbed function of the underlying STUB1 gene, which translates into a multidimensional gradual spectrum of variably associated clinical signs and symptoms.
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