RNASE4 – Amyotrophic Lateral Sclerosis

The association between RNASE4 and amyotrophic lateral sclerosis (ALS) is supported by several independent in silico and functional studies. Multiple reports have evaluated the role of rare RNASE4 variants in ALS patient cohorts, with analyses indicating that around 20 reported rare variants include approximately five variants predicted to cause loss-of-function effects (PMID:30544007).

While the genetic data stem primarily from computational analyses and molecular dynamics simulations rather than large-scale family studies or extensive segregation data, the recurrence of deleterious RNASE4 variants across independent studies provides moderate genetic support. The evidence is limited by the absence of comprehensive proband counts and familial segregation information to further bolster the association (PMID:31368019).

Genetic evidence focuses on the identification of missense and other rare variants in RNASE4. For example, one study reported a panel of about 20 rare RNASE4 variants, of which five variants were predicted to abrogate ribonucleolytic function; however, no variant is currently described using a complete coding HGVS description such as a c. notation. Accordingly, the list of reported variants for RNASE4 remains empty in the present summary.

The functional studies provide additional insight into the pathogenic mechanism. Multiple molecular dynamics simulations and in vitro functional assays have demonstrated that RNASE4 variants (for instance, those affecting amino acids such as Glutamic acid at position 48) disrupt the catalytic activity of the enzyme, consistent with a loss‑of‑function mechanism (PMID:29279004). This functional concordance, though promising, is tempered by the limited clinical data linking these variants directly to ALS in patients.

There is no significant conflicting evidence reported; however, the current body of work is predominantly based on in silico analyses and lacks robust segregation data. Therefore, caution is warranted when interpreting the clinical utility of RNASE4 testing. Further multi‑center studies with additional affected family members are needed to firmly establish the gene‑disease relationship.

In summary, although functional studies consistently support a loss‑of‑function mechanism in RNASE4 that could contribute to ALS, the genetic evidence remains limited by small-scale variant analyses and minimal segregation data. Key take‑home message: RNASE4 represents a promising target for further research into ALS, but additional clinical validation is essential for diagnostic and therapeutic applications.

References

• Metabolic Brain Disease • 2019 • Rare Angiogenin and Ribonuclease 4 variants associated with amyotrophic lateral sclerosis exhibit loss‑of‑function: a comprehensive in silico study PMID:31368019
• Mutation Research • 2019 • A molecular dynamics based investigation reveals the role of rare Ribonuclease 4 variants in amyotrophic lateral sclerosis susceptibility PMID:30544007
• Journal of Biomolecular Structure & Dynamics • 2019 • Insights into the role of ribonuclease 4 polymorphisms in amyotrophic lateral sclerosis PMID:29279004

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