CCNF – Amyotrophic Lateral Sclerosis

Multiple independent studies have identified heterozygous missense mutations in CCNF (HGNC:1591) in patients diagnosed with amyotrophic lateral sclerosis (ALS) (MONDO:0004976). Genetic analyses performed in diverse cohorts, including a Taiwanese series in which two novel variants were reported in separate ALS cases (PMID:29102476), and an Italian cohort where CCNF variants were identified in 16 index cases (PMID:39766833), underpin the association between CCNF variants and ALS. These studies, together with case reports that note CCNF alterations in both familial and sporadic cases, emphasize a robust genetic contribution to disease susceptibility.

Genetic evidence demonstrates that variants such as c.664T>C (p.Ser222Pro) are recurrently identified in ALS patients, suggesting that alteration of CCNF gene dosage or function plays a critical role in disease pathogenesis. Further, the reported mutational spectrum includes a range of missense alterations, and the identification of these variants has been facilitated by systematic sequencing approaches in well‐characterized cohorts (PMID:29102476, PMID:28281833).

Experimental studies provide compelling functional data in support of a pathogenic mechanism. In vitro assays have shown that CCNF mutations (for example, c.1861A>G (p.Ser621Gly)) result in hyper‑ubiquitylation, impaired autophagy, and abnormal subcellular protein localization, findings that resonate with the proteostasis defects observed in ALS (PMID:29021214, PMID:28852778). Additionally, investigations into mutant CCNF effects on the ubiquitin‑proteasome system and co‑factors such as VCP further corroborate its disruptive impact on neuronal homeostasis (PMID:31577344).

The integration of genetic and experimental evidence strongly supports a pathogenic role of CCNF alterations in the etiology of ALS. The consistent detection of CCNF variants in both familial and sporadic patients, combined with molecular data delineating specific proteostatic defects, provides a basis for employing CCNF mutation analysis as part of the diagnostic workup for ALS. Such an approach may improve early detection and guide personalized management strategies in clinical settings.

Key Take‑home: Incorporating CCNF genetic testing can enhance ALS diagnostic accuracy and offers actionable insights for targeted therapeutic strategies.

References

• Current Alzheimer research • 2023 • Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report PMID:37872794
• Neurobiology of aging • 2018 • Investigating CCNF mutations in a Taiwanese cohort with amyotrophic lateral sclerosis PMID:29102476
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2017 • Mutations of CCNF gene is rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia from Mainland China PMID:28281833
• Open biology • 2017 • Casein kinase II phosphorylation of cyclin F at serine 621 regulates the Lys48-ubiquitylation E3 ligase activity of the SCF(cyclin F) complex PMID:29021214
• Cellular and molecular life sciences : CMLS • 2018 • Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy PMID:28852778
• Human molecular genetics • 2019 • Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity PMID:31577344
• Life science alliance • 2022 • ALS-linked loss of Cyclin-F function affects HSP90 PMID:36114006

Evidence Based Scoring (AI generated)