ArticleHuman molecular genetics2014
Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
93 citing papers in PubMed, 147 citations in OpenAlex.
- Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis.bioRxiv : the preprint server for biology · 2026Article
- Domain-dependent uncoupling of the co-chaperone and E3 ubiquitin ligase CHIP underlies heterogeneity in spinocerebellar ataxia 48.The Journal of biological chemistry · 2026Article
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- Clinical and Genetic Profile of Gordon-Holmes Syndrome: A Review of Published Cases : Original Article.Cerebellum (London, England) · 2026Review
- E3 ubiquitin ligases: structural diversity, dysregulation in disease, and their emerging role in targeted therapeutic strategies.Frontiers in molecular biosciences · 2026Review
- A protocol to establish and maintain organotypic cerebellar slice culture (OCerSC) from aged mice.PloS one · 2026Article
- Review
- CHIP protects lysosomes from CLN4 mutant-induced membrane damage.Nature cell biology · 2025Article
- A STUB1-CHIC2 complex inhibits CD8Nature immunology · 2025Article
- STUB1-Associated Autosomal-Recessive Spinocerebellar Ataxia Type 16 (SCAR16) Presenting with Gordon-Holmes Syndrome Caused by Maternal Uniparental Isodisomy.Movement disorders clinical practice · 2025Article
- E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.The EMBO journal · 2025Article
- Clinical and functional characterization of a novel STUB1 mutation in a Chinese spinocerebellar ataxia 48 pedigree.Orphanet journal of rare diseases · 2024Article
- A Chinese Family with Digenic TBP/STUB1 Spinocerebellar Ataxia.Cerebellum (London, England) · 2024Article
- Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.Cerebellum (London, England) · 2024Review
- Article
- Die Hard: Necroptosis and its Impact on Age-Dependent Neuroinflammatory Diseases.Frontiers in cell death · 2024Article
- A novel mutation inBMJ case reports · 2023Article
- Article
- STUB1 directs FOXQ1-mediated transactivation of Ldha gene and facilitates lactate production in mouse Sertoli cells.Cell and tissue research · 2023Article
- Activity-based probe profiling of RNF12 E3 ubiquitin ligase function in Tonne-Kalscheuer syndrome.Life science alliance · 2022Article
33 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
16 authors at 4 institutions in 2 countries.
Funding
Abstract
Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.