CCNF was first reported in relation to autosomal dominant ALS-FTD in a large family of British ancestry through linkage analysis (Williams et al., 2016, PMID: 27080313). Linkage analysis revealed a candidate region at 16p13.3-p12.3, which was determined to be a novel mutation in CCNF (Ser621Gly) by exome sequencing. CCNF codes for the Cyclin F protein, a component of an E3 ubiquitin–protein ligase (F box protein family) (Skp1-Cul1-F-box) that is involved in mediating the ubiquitination and consequently degradation of target proteins through the ubiquitin proteasome system. At least 37 variants in the CCNF gene have since been reported to cause ALS-FTD in humans of diverse geoancestry across five publications (PMIDs: 27080313, 29102476, 30008669, 28281833, 31475037). However, several reported variants have relatively high minor allele frequencies in population databases (>0.000005) and were not scored as genetic-level evidence. Overall evidence supporting the CCNF gene-disease relationship includes case-level data and experimental data. Mutant Cyclin F (Ser621Gly) has been shown to disrupt Lys48-specific ubiquitylation, resulting in accumulation of RRM2 and TDP43 (PMID: 28852778). The mutant protein interacts with p62/SQSTM1 and leads to defects in autophagic degradation (PMID: 28852778). Additionally, mutant Cyclin F has been shown to cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity (which promotes cytoplasmic aggregation of TDP-43) (PMID: 31577344). Finally, mutant Cyclin F (Ser621Gly) has been shown to cause disruption of axonal outgrowth, increased cell death in the spinal cord, and aberrant motor phenotype in Zebrafish (PMID: 28444311). In summary, due to limited scorable genetic-level evidence and lack of a strong model system to demonstrate the phenotype of mutant CCNF, there is currently limited evidence to support a gene-disease relationship between CCNF and ALS-FTD. This classification was approved by the ClinGen ALS GCEP on February 8, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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