RNF216 and Cerebellar Ataxia-Hypogonadism Syndrome

RNF216 pathogenic variants are strongly associated with cerebellar ataxia-hypogonadism syndrome, a clinical entity often referred to as Gordon Holmes syndrome. Affected individuals typically present with a constellation of neurological deficits including ataxia, progressive cognitive decline, and hypogonadism, alongside additional features such as azoospermia, cerebellar atrophy, and dystonia (PMID:35088240).

The inheritance pattern is autosomal recessive, as demonstrated by multiple family studies in which segregating RNF216 variants were observed among affected relatives (PMID:27441066). Detailed segregation analyses across independent pedigrees support the causative role of these variants.

Genetic evidence has emerged from several case reports and multi‐patient studies documenting a diverse spectrum of mutations in RNF216. One notable example is the novel homozygous nonsense mutation, c.1948G>T (p.Glu650Ter), identified in a patient with classic features of the syndrome (PMID:35088240). Other mutation types including frameshift and potential splicing variants have been reported, further underscoring the genetic heterogeneity of this disorder (PMID:37161390, PMID:37977846).

Multi‐patient studies have reinforced these findings by demonstrating segregation in several families, with additional affected relatives collectively numbering in the low double‐digits. The recurrent observation of RNF216 mutations across diverse ethnic backgrounds supports its critical role in disease pathogenesis and explains the variability in clinical presentation, which ranges from ataxia and hypogonadism to cognitive impairment and parkinsonism.

Experimental evidence further corroborates the clinical data. Functional assays, including zebrafish knockdown studies and in vitro ubiquitination assessments, have shown that RNF216 mutations result in impaired K63‐linked ubiquitination. Given the importance of this non‐degradative ubiquitin chain in neuronal signaling, these findings provide a compelling mechanism linking RNF216 loss‐of‐function to the neurodegenerative and endocrine features observed in patients (PMID:23656588, PMID:31087003).

In summary, convergent genetic and functional evidence from multiple independent studies supports a strong association between RNF216 mutations and cerebellar ataxia-hypogonadism syndrome. Although additional modifiers may influence the full phenotypic spectrum, the current data justify the inclusion of RNF216 genetic testing in patients exhibiting overlapping neurological and reproductive abnormalities.

Key take‑home: Recognizing RNF216 mutations as a causative factor in cerebellar ataxia-hypogonadism syndrome can substantially improve diagnostic accuracy and guide clinical management.

References

• Journal of molecular neuroscience : MN • 2022 • Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome PMID:35088240
• BMC medical genomics • 2023 • A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome PMID:37161390
• BMJ case reports • 2023 • A novel mutation in RNF216 gene in an Indian case with Gordon Holmes syndrome PMID:37977846
• Neurology international • 2016 • Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation PMID:27441066
• The New England journal of medicine • 2013 • Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination PMID:23656588
• Human molecular genetics • 2019 • Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome PMID:31087003

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