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The association between RTN2 and hereditary spastic paraplegia (MONDO_0019064) is supported by multiple independent studies that consistently demonstrate a strong link between the gene and the disease phenotype (PMID:22232211, PMID:38291924). These studies document autosomal dominant inheritance and report pathogenic variants in RTN2 across unrelated probands, reinforcing the clinical validity of the association. The accumulation of genetic data from diverse populations further supports its application in diagnostic decision‑making, commercial assay development, and future research publication.
Genetic evidence has been gathered from several case reports and patient series, demonstrating a broad variant spectrum that includes truncating, frameshift, and splice site mutations. A representative variant, c.926del (p.Gly309fs), was reported in a family with autosomal dominant hereditary spastic paraplegia (PMID:22232211). In addition, cohorts from subsequent studies identified multiple pathogenic variants, with several families showing clear segregation of the mutant allele with the disease. This genetic heterogeneity underscores the clinical relevance of RTN2 screening and the necessity of incorporating its analysis in genetic panels for HSP.
Autosomal dominant inheritance is the predominant mode observed in families with RTN2 mutations. Segregation analysis in these reports has identified additional affected relatives in several pedigrees, supporting a consistent familial transmission pattern (PMID:22232211). Patients typically present with progressive lower limb spasticity and corticospinal tract degeneration, phenotypes that are characteristic of hereditary spastic paraplegia and corroborated across independent clinical series (PMID:38716326).
Functional studies have provided important insights into the pathogenic mechanism underlying RTN2-related HSP. Experimental assays demonstrated that RTN2 is essential for maintaining endoplasmic reticulum (ER) morphology by interacting with other ER-shaping proteins such as spastin. Frameshift and truncating mutations disrupt RTN2 protein localization and lead to loss of proper ER architecture, which is believed to contribute to axonal degeneration (PMID:35684947). These findings directly link the molecular consequences of RTN2 disruption to the clinical manifestations observed in HSP patients.
In summary, the integrated genetic and functional evidence firmly supports a strong association between RTN2 and hereditary spastic paraplegia. Although additional supporting data exist beyond the established scoring maximum, the available evidence, including clear autosomal dominant segregation and consistent functional impairment, is sufficiently robust for clinical and commercial applications. The compelling dataset provides essential guidance for utilizing RTN2 variant screening in the diagnostic evaluation of patients with suspected HSP.
Key Take‑home Sentence: The strong and multifaceted evidence supporting RTN2 mutations in autosomal dominant hereditary spastic paraplegia makes RTN2 a critical target for genetic testing and therapeutic investigation.
Gene–Disease AssociationStrongEvidence from multiple independent studies demonstrates autosomal dominant inheritance with over eight unrelated probands showing RTN2 mutations and familial segregation (PMID:22232211, PMID:38291924). Genetic EvidenceStrongNumerous variant types, including truncating and frameshift mutations such as c.926del (p.Gly309fs), have been identified in independent cohorts, with clear segregation in affected families (PMID:22232211). Functional EvidenceModerateFunctional assays demonstrate that RTN2 mutations disrupt ER morphology and protein localization, impairing interactions with key ER-shaping proteins, which supports the observed disease phenotype (PMID:35684947). |