ArticleThe New England journal of medicine2013
Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.
Article in The New England journal of medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 1 of them a synthesis that pooled it.
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Who cites it
130 citing papers in PubMed, 1 synthesis or guideline pooled it, 230 citations in OpenAlex.
- Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes.Acta neuropathologica · 2023Pooled it
- Substrate Profiling of RNF216 Uncovers a Translation-Linked OTUD4 Regulatory Axis.bioRxiv : the preprint server for biology · 2026Article
- Human Gordon Holmes Syndrome modeling in mice reveals essential function of RNF216 ubiquitination in spermatogenesis and male fertility.Genes & diseases · 2026Article
- Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas.eLife · 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
- OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis.Neoplasia (New York, N.Y.) · 2026Article
- Review
- Bi-allelic deleterious variants in SNAPIN, which encodes a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder.American journal of human genetics · 2025Article
- Differential Transcript Expression and Alternative RNA Splicing Patterns to Differentiate Focal vs. Generalized-Onset Seizures.Molecular neurobiology · 2025Article
- Identification of a large homozygous RNF216 deletion in a Chinese patient with gordon holmes syndrome.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Identification of Novel Genetic Variants in a Cohort of Congenital Hypogonadotropic Hypogonadism: Computational Analysis of Pathogenicity Predictions.International journal of molecular sciences · 2025Article
- The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway.Cell reports · 2025Article
- RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.Nature communications · 2025Article
- Rescuing DNMT1 fails to fully reverse the molecular and functional repercussions of its loss in mouse embryonic stem cells.Nucleic acids research · 2025Article
- Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.Psychiatry and clinical neurosciences · 2025Article
- Hypogonadotropic Hypogonadism as First Presentation of the Severe Neuroendocrine Disorder Caused by RNF216.JCEM case reports · 2024Article
- Disorders of puberty and neurodevelopment: A shared etiology?Annals of the New York Academy of Sciences · 2024Review
- The role of ubiquitination in health and disease.MedComm · 2024Review
- The autophagy adaptor TRIAD3A promotes tau fibrillation by nested phase separation.Nature cell biology · 2024Article
70 more citing papers are in PubMed but not listed here.
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Authors and funding
21 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundThe combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.
methodsWe performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.
resultsDigenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis.
conclusionsThe syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).
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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.