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CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Williams KL, Topp S, Yang S, Smith B, Fifita JA, Warraich ST, Zhang KY, Farrawell N, Vance C, Hu X, Chesi A, Leblond CS, Lee A, Rayner SL, Sundaramoorthy V, Dobson-Stone C, Molloy MP, van Blitterswijk M, Dickson DW, Petersen RC, Graff-Radford NR, Boeve BF, Murray ME, Pottier C, Don E, Winnick C, McCann EP, Hogan A, Daoud H, Levert A, Dion PA, Mitsui J, Ishiura H, Takahashi Y, Goto J, Kost J, Gellera C, Gkazi AS, Miller J, Stockton J, Brooks WS, Boundy K, Polak M, Muñoz-Blanco JL, Esteban-Pérez J, Rábano A, Hardiman O, Morrison KE, Ticozzi N, Silani V, de Belleroche J, Glass JD, Kwok JB, Guillemin GJ, Chung RS, Tsuji S, Brown RH, García-Redondo A, Rademakers R, Landers JE, Gitler AD, Rouleau GA, Cole NJ, Yerbury JJ, Atkin JD, Shaw CE, Nicholson GA, Blair IP - Nat Commun (2016)

Bottom Line: CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)).Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate.This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.

ABSTRACT
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

No MeSH data available.


Related in: MedlinePlus

CCNF mutations in ALS-FTD identified following genetic linkage analysis and exome sequencing.(a) Pedigree of family FALS10. All family members from whom DNA was available for genotyping are indicated by either wild type (WT) for CCNF, or by mutation in CCNF (‘S621G'). Individuals with ALS are represented by a black-filled symbol, individuals with FTD by a grey-filled symbol. Arrows indicate samples used for exome sequencing. (b) Sequence traces of WT and c.1861A>G mutation identified in family FALS10. (c) Diagrammatic representation of cyclin F protein and the location of novel mutations identified in this study. Cyclin F contains three functional modules within its protein structure. The F-box domain forms a ‘pseudocatalytic' module, the two cyclin domains form the substrate recruitment module and the C terminus contains both a nuclear localization signal (NLS) and a PEST sequence (short stretch of amino acids enriched in proline, glutamic acid, serine and threonine) that form the regulatory module16. (d) Multiple sequence alignment of cyclin F across species showing evolutionary conservation of the substituted amino-acid residues (indicated by arrows). Sequences include NP_001752.2 (human), NP_001252844.1 (chimpanzee), NP_031660.3 (mouse), NP_001093944.1 (rat), NP_001092340.1 (cow), NP_001079901.1 (frog) and NP_996931.1 (zebrafish).
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f1: CCNF mutations in ALS-FTD identified following genetic linkage analysis and exome sequencing.(a) Pedigree of family FALS10. All family members from whom DNA was available for genotyping are indicated by either wild type (WT) for CCNF, or by mutation in CCNF (‘S621G'). Individuals with ALS are represented by a black-filled symbol, individuals with FTD by a grey-filled symbol. Arrows indicate samples used for exome sequencing. (b) Sequence traces of WT and c.1861A>G mutation identified in family FALS10. (c) Diagrammatic representation of cyclin F protein and the location of novel mutations identified in this study. Cyclin F contains three functional modules within its protein structure. The F-box domain forms a ‘pseudocatalytic' module, the two cyclin domains form the substrate recruitment module and the C terminus contains both a nuclear localization signal (NLS) and a PEST sequence (short stretch of amino acids enriched in proline, glutamic acid, serine and threonine) that form the regulatory module16. (d) Multiple sequence alignment of cyclin F across species showing evolutionary conservation of the substituted amino-acid residues (indicated by arrows). Sequences include NP_001752.2 (human), NP_001252844.1 (chimpanzee), NP_031660.3 (mouse), NP_001093944.1 (rat), NP_001092340.1 (cow), NP_001079901.1 (frog) and NP_996931.1 (zebrafish).

Mentions: To identify novel ALS loci, we performed two independent genome-wide scans for linkage in an Australian multi-generational family (FALS10, historically of UK ancestry) comprising 10 individuals with ALS and/or FTD (Fig. 1a). The family displays autosomal dominant inheritance of disease and mutations in all known ALS genes were excluded. The first genome-wide scan for linkage, which used 10 K Affymetrix single-nucleotide polymorphism (SNP) arrays, implicated candidate loci with maximum multipoint LOD scores >1.9 but <3, on chromosomes 11p15.4-p14.3, 16p13.3-p12.3 and 20p13-p12.2, respectively (Supplementary Fig. 1b). The second genome-wide scan for linkage, which used 539 microsatellite markers, generated LOD scores >3.0 at a single candidate region on chromosome 16 (maximum genome-wide two-point LOD score of 3.16, θ=0, at D16S3065) that overlapped the chromosome 16 interval identified by the initial, SNP-based, linkage scan (Supplementary Fig. 1a). Fine mapping and recombinant haplotype analysis using a dense coverage of microsatellite markers spanning the chromosome 16 interval refined the minimal candidate region to 7.5 Mb on chromosome 16p13.3 flanked by D16S521 and D16S418, with a maximum two-point LOD score of 3.24, θ=0, at D16S3082 (Supplementary Table 1). Multipoint linkage analysis of the 7.5 Mb disease haplotype indicated LOD scores >3 across the entire linked disease interval (Supplementary Fig. 1c). In summary, unbiased genome-wide linkage analysis in family FALS10 identified a single novel familial ALS/FTD locus on chromosome 16p13.3.


CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Williams KL, Topp S, Yang S, Smith B, Fifita JA, Warraich ST, Zhang KY, Farrawell N, Vance C, Hu X, Chesi A, Leblond CS, Lee A, Rayner SL, Sundaramoorthy V, Dobson-Stone C, Molloy MP, van Blitterswijk M, Dickson DW, Petersen RC, Graff-Radford NR, Boeve BF, Murray ME, Pottier C, Don E, Winnick C, McCann EP, Hogan A, Daoud H, Levert A, Dion PA, Mitsui J, Ishiura H, Takahashi Y, Goto J, Kost J, Gellera C, Gkazi AS, Miller J, Stockton J, Brooks WS, Boundy K, Polak M, Muñoz-Blanco JL, Esteban-Pérez J, Rábano A, Hardiman O, Morrison KE, Ticozzi N, Silani V, de Belleroche J, Glass JD, Kwok JB, Guillemin GJ, Chung RS, Tsuji S, Brown RH, García-Redondo A, Rademakers R, Landers JE, Gitler AD, Rouleau GA, Cole NJ, Yerbury JJ, Atkin JD, Shaw CE, Nicholson GA, Blair IP - Nat Commun (2016)

CCNF mutations in ALS-FTD identified following genetic linkage analysis and exome sequencing.(a) Pedigree of family FALS10. All family members from whom DNA was available for genotyping are indicated by either wild type (WT) for CCNF, or by mutation in CCNF (‘S621G'). Individuals with ALS are represented by a black-filled symbol, individuals with FTD by a grey-filled symbol. Arrows indicate samples used for exome sequencing. (b) Sequence traces of WT and c.1861A>G mutation identified in family FALS10. (c) Diagrammatic representation of cyclin F protein and the location of novel mutations identified in this study. Cyclin F contains three functional modules within its protein structure. The F-box domain forms a ‘pseudocatalytic' module, the two cyclin domains form the substrate recruitment module and the C terminus contains both a nuclear localization signal (NLS) and a PEST sequence (short stretch of amino acids enriched in proline, glutamic acid, serine and threonine) that form the regulatory module16. (d) Multiple sequence alignment of cyclin F across species showing evolutionary conservation of the substituted amino-acid residues (indicated by arrows). Sequences include NP_001752.2 (human), NP_001252844.1 (chimpanzee), NP_031660.3 (mouse), NP_001093944.1 (rat), NP_001092340.1 (cow), NP_001079901.1 (frog) and NP_996931.1 (zebrafish).
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f1: CCNF mutations in ALS-FTD identified following genetic linkage analysis and exome sequencing.(a) Pedigree of family FALS10. All family members from whom DNA was available for genotyping are indicated by either wild type (WT) for CCNF, or by mutation in CCNF (‘S621G'). Individuals with ALS are represented by a black-filled symbol, individuals with FTD by a grey-filled symbol. Arrows indicate samples used for exome sequencing. (b) Sequence traces of WT and c.1861A>G mutation identified in family FALS10. (c) Diagrammatic representation of cyclin F protein and the location of novel mutations identified in this study. Cyclin F contains three functional modules within its protein structure. The F-box domain forms a ‘pseudocatalytic' module, the two cyclin domains form the substrate recruitment module and the C terminus contains both a nuclear localization signal (NLS) and a PEST sequence (short stretch of amino acids enriched in proline, glutamic acid, serine and threonine) that form the regulatory module16. (d) Multiple sequence alignment of cyclin F across species showing evolutionary conservation of the substituted amino-acid residues (indicated by arrows). Sequences include NP_001752.2 (human), NP_001252844.1 (chimpanzee), NP_031660.3 (mouse), NP_001093944.1 (rat), NP_001092340.1 (cow), NP_001079901.1 (frog) and NP_996931.1 (zebrafish).
Mentions: To identify novel ALS loci, we performed two independent genome-wide scans for linkage in an Australian multi-generational family (FALS10, historically of UK ancestry) comprising 10 individuals with ALS and/or FTD (Fig. 1a). The family displays autosomal dominant inheritance of disease and mutations in all known ALS genes were excluded. The first genome-wide scan for linkage, which used 10 K Affymetrix single-nucleotide polymorphism (SNP) arrays, implicated candidate loci with maximum multipoint LOD scores >1.9 but <3, on chromosomes 11p15.4-p14.3, 16p13.3-p12.3 and 20p13-p12.2, respectively (Supplementary Fig. 1b). The second genome-wide scan for linkage, which used 539 microsatellite markers, generated LOD scores >3.0 at a single candidate region on chromosome 16 (maximum genome-wide two-point LOD score of 3.16, θ=0, at D16S3065) that overlapped the chromosome 16 interval identified by the initial, SNP-based, linkage scan (Supplementary Fig. 1a). Fine mapping and recombinant haplotype analysis using a dense coverage of microsatellite markers spanning the chromosome 16 interval refined the minimal candidate region to 7.5 Mb on chromosome 16p13.3 flanked by D16S521 and D16S418, with a maximum two-point LOD score of 3.24, θ=0, at D16S3082 (Supplementary Table 1). Multipoint linkage analysis of the 7.5 Mb disease haplotype indicated LOD scores >3 across the entire linked disease interval (Supplementary Fig. 1c). In summary, unbiased genome-wide linkage analysis in family FALS10 identified a single novel familial ALS/FTD locus on chromosome 16p13.3.

Bottom Line: CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)).Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate.This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.

ABSTRACT
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

No MeSH data available.


Related in: MedlinePlus