FANCC Gene

Alternative Names

  • FANCC
  • FAC
  • FACC
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OMIM Number

613899

Gene Map Locus
9q22.32

Description

The FANCC gene encodes a product that is involved in the homologous recombination repair of damaged DNA through the Fanconi anaemia (FA) pathway.  It does this by forming a multi-subunit complex with FANCA, FANCB, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM called the FA core complex.  This complex ubiquitinates FANCD2 and FANCI, causing them to bind together and attract DNA repair proteins to the area of DNA damage.

Mutations in the FANCC gene impair protein function, thereby affecting the FA core complex and disrupting the FA pathway.  This results in inefficient DNA repair and a build-up of inter-strand crosslinks ultimately stalling DNA replication and causing either abnormal cell death or uncontrolled cell growth.  Abnormal cell death leads to blood cell shortage and manifests as Fanconi anaemia while uncontrolled cell growth develops into leukemia or other cancers.  Mutations in the FANCC gene are therefore associated with Fanconi anaemia, complementation group C.  Fanconi anaemia is a rare blood disorder that results in bone marrow failure, organ defects, physical abnormalities and susceptibility to certain cancers.

Molecular Genetics

The FANCC gene is made up of 22 exons and is about 218 kb long.  The protein product encoded by the gene is 63 kDa in size and made up of 558 amino acids.  About 15% of Fanconi anaemia cases are caused by mutations in the FANCC gene.  So far, more than 50 homozygous or compound heterozygous FANCC mutations have been linked to the disorder.  Most of these mutations result in a reduced or null protein function. The mutation 456+4A>T, found in Ashkenazi Jewish populations, has a particularly severe phenotype compared to other FANCC mutations.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Ghazwani et al. (2016) recruited all the Fanconi anaemia (FA) affected patients at a Saudi Arabian hospital to carry out a genetic analysis.  Of these, one 5-year old female patient presented with growth retardation, microcephaly, hypopigmentation and tracheoesophageal fistula.  At the age of four, she presented with severe aplastic anaemia.  She did not have any malignancies or a family history of cancer.  Genetic testing revealed a novel homozygous mutation c.1475T>C in the FANCC gene, resulting in a p.Leu492Pro substitution.  The variant was not found in 50 Saudi non-FA controls and was predicted by in-situ analysis to be disease causing.  It is important to note that except for FANCC, most Saudi FA mutations were found to occur in downstream FA pathway genes.  This is in contrast with European patients where 90% of FA cases involve genes required for FANCD2/FANCI monoubiquitination.  Thus, the FANCD2 monoubiquitination assay was considered ineffective in diagnosing most Saudi FA cases. 

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