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CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Journal Article


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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 (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

Authors


  •   Williams, Kelly L. (external author)
  •   Topp, Simom (external author)
  •   Yang, Shu (external author)
  •   Smith, Bradley (external author)
  •   Fifita, Jennifer A. (external author)
  •   Warraich, Sadaf T. (external author)
  •   Zhang, Katharine Y. (external author)
  •   Farrawell, Natalie E.
  •   Vance, Caroline (external author)
  •   Hu, Xun (external author)
  •   Yerbury, Justin J.

Publication Date


  • 2016

Citation


  • Williams, K. L., Topp, S., Yang, S., Smith, B., Fifita, J. A., Warraich, S. T., Zhang, K. Y., Farrawell, N., Vance, C., Hu, X., Yerbury, J. J. et al (2016). CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nature Communications, 7 (April), 11253-1-11253-8.

Scopus Eid


  • 2-s2.0-84964430150

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1821&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/798

Start Page


  • 11253-1

End Page


  • 11253-8

Volume


  • 7

Issue


  • April

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 (SCFCyclin F). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCFCyclin F substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

Authors


  •   Williams, Kelly L. (external author)
  •   Topp, Simom (external author)
  •   Yang, Shu (external author)
  •   Smith, Bradley (external author)
  •   Fifita, Jennifer A. (external author)
  •   Warraich, Sadaf T. (external author)
  •   Zhang, Katharine Y. (external author)
  •   Farrawell, Natalie E.
  •   Vance, Caroline (external author)
  •   Hu, Xun (external author)
  •   Yerbury, Justin J.

Publication Date


  • 2016

Citation


  • Williams, K. L., Topp, S., Yang, S., Smith, B., Fifita, J. A., Warraich, S. T., Zhang, K. Y., Farrawell, N., Vance, C., Hu, X., Yerbury, J. J. et al (2016). CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia. Nature Communications, 7 (April), 11253-1-11253-8.

Scopus Eid


  • 2-s2.0-84964430150

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1821&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/798

Start Page


  • 11253-1

End Page


  • 11253-8

Volume


  • 7

Issue


  • April