Technical information on . . .

Fanconi Anemia Genes

Overview

This page presents technical information on the known FA genes--gene location, size, etc.  It also has links to even more detailed information on the genes. You'll find that these additional sources contain yet additional links to even more information, and much of it is cross-linked to each other.  If you follow the links far enough, you can even obtain the reference genetic sequence for each gene. 

This information is useful if you are pursuing a mutation analysis to determine the specific mutations that are affecting your family.

The Fanconi Anemia Mutation Database maintains a databasse of know mutations of the known Fanconi Anemia genes.  As investigators identify new mutations, they are submitted to this database.  The database also maintains a list of known polymorphisms (these aren't pathogenic, as they do not cause the Fanconi Anemia disease).

Contents

FANCA gene
FANCB gene
FANCC gene
FANCD1 gene
FANCD2 gene
FANCE gene
FANCF gene
FANCG gene
FANCI gene
FANCJ gene
BRCA2 gene
FANCL gene
FANCM gene

FANCA Gene

Comments
    Pathogenic mutations of FANCA are the most common cause of Fanconi Anemia, accounting for 65-70% of all cases.  Greater than 100 mutations have been identified which are scattered throughout the gene. A high frequency of intragenic deletions have been detected, which remove between 1 and 30 exons of the gene. It is thought that many more mutations remain to be discovered; as a result, families may have "private" mutations that aren't yet a known mutation. 

One recent article looked at 21 different mutations to see how the mutations affected sensitivity to mitomycin C (MMC), protein expression, interaction with other FA proteins (C, F, G, and D2), and degree of phosporylation. The researchers were able to classify the mutations into three grades: Group 1 (5 proteins) behaved like wild-type FANCA, Group 2 (4 proteins) were mildly impaired, and Group 3 (12 proteins) were severely impaired.  The different amount of impairment may partly account for the phenotypic varation (the different severity of the disease) see in FA patients.  Note that Group 1 proteins apparantly worked like normal FANCA proteins--it is speculated that they may be pathogenic by reducing endogenous expression or perhaps they are really benign polymorphisms.
source: Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants, by Daiki Adachi, Tsukasa Oda, Hiroshi Yagasaki, Keiko Nakasato, Toshiyasu Taniguchi, Alan D. D'Andrea, Shigetaka Asano, and Takayuki Yamashita; Human Molecular Genetics, 2002, Vol 11, No. 25, pages 3125-3134.

FANCB Gene

Comments - The discovery of this gene was announced October 24, 2004 in Nature Genetics. Also see the section on BRCA2--recent research points towards a role of BRCA2 in the "B" complementation group. Also check the OMIM entry for the latest information.

The X-linked inheritance breaks the pattern of Fanconi anemia being an autosomal recessive disorder. X is a sex chromosome, not an autosomal chromosome. All known FA-B patients are males. FA-B patients receive the disease-causing chromosome from their mother (although, if a FA-B male was the father, it could come from him). Each son of a carrier mother has a 50% chance of inheriting the disease and each daughter has a 50% chance of being a carrier.

Read articles about the discovery:
X-linked inheritance of Fanconi anemia complementation group B, by Meetei et all, Nature Genetics 36, 1219-1224 (2004), published 24 October 2004.

A new gene on the X involved in Fanconi Anemia, by Nazeen Rahman & Alan Ashworth, Nature Genetics 36, 1142-1143 (2004)

FANCC Gene

Comments
   As the first FA gene identified, much information has accumulated about it.  Ten (10) pathogenic mutations account for the majority of FANCC mutations.  The most frequent mutation is an A-to-T transition in intron 4 (IVS4+4A®T) resulting in an abnormal splice site. The majority of patients with this mutation are of Ashkenazi Jewish ancestry (carrier frequency of 1 in 150) and tended to display a severe phenotype manifested by multiple major congential malformations and early onset (median age 2.7 years) of bone marrow failure. Similarly, patients with the exon 14 (L554P) mutation had a severe phenotype. Patients with mutations in exon 1 (322delG and Q13X) and exon 6 (R185X) (Nothern European ancestry) tended to have mild phenotypes with fewer somatic abnormalities and a later onset (median age 7.6 years) of bone marrow failure. Survival rates are correlated to onset of bone marrow failure; prior IVS4 and exon 14 patients had a median survival rate of 14.9 and 9.7 years, respectively.  In contrast, prior exon 1 patients had a median survival of 19.7 years.

14 May 2003: FANCC and FANCG have been linked (weakly) to pancreatic cancer. See the report Hopkins Scientists Uncover Role Of Fanconi's Anemia Genes In Pancreatic Cancer. See this page on Dr. Alter's perspective on this research.

FANCD1 Gene - See BRCA2 information

Comment - see the BRCA2 entry -- the BRCA2 gene is the previously unidentified FANCD1 gene!

FANCD2 Gene

The protein is expressed as two isoforms, FANCD2-L (long) and FANCD2-S (short) with apparant molecular weights of 162 and 155 kDa respectively. Approximately 5 pathogenic mutations have been discovered.

FANCE Gene

Approximately 3 pathogenic mutations have been discovered.

FANCF Gene

Approximately 6 pathogentic mutations have been discovered.

FANCG Gene

FANCG was found to be identical to XRCC9, a gene defective in radiation sensitive Chinese hamster ovary cells.  Approximately 18 pathogenic mutations have been discovered.

14 May 2003: FANCC and FANCG have been linked (weakly) to pancreatic cancer. See the report Hopkins Scientists Uncover Role Of Fanconi's Anemia Genes In Pancreatic Cancer. See this page on Dr. Alter's perspective on this research.

FANCI Gene

OMIM entry 609053

Reported in January 2003; have not seen any published information on this gene yet

FANCJ Gene

OMIM entry 609054

Comments - Also called BRIP1 and BACH1.

Read about the discovery of the gene here:
The BRCA1-interacting helicase BRIP1 is deficient in Fanconi Anemia, by Orna Levran et al; Nature Genetics 37, 931-933 (2005). Published online 21 August 2005.

The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J, by Marieke Levitus et al; Nature Genetics 37, 934-935 (2005). Published online 21 August 2005.

The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair, by Wendy L Bridge et al; Nature Genetics 37, 953-957 (2005). Published online 21 August 2005.

BRCA2 Gene

Comments
   This gene, "Breast Cancer 2, early onset" was discovered in 1995 as a gene than can cause inherited susceptibility to early onset of breast cancer.  In 2002, it was discovered that inheriting two mutated copies of the BRCA2 gene can cause Fanconi Anemia--in fact, BRCA2 is the previously unidentified FANCD1 gene. The research that discovered  this was partially supported by the Fanconi Anemia Research Fund. 

Read the article of the discovery: Biallelic Mutations of BRCA2 Cause Fanconi Anemia [PDF file format]
Read also commentary on the article: D-Day for BRCA2 [PDF File format]

FANCL/PHF9/POG Gene

Comments
   Reported 14-Sep-03 in Nature Genetics in a letter entitled, "A novel ubiquitin ligase is deficient in Fanconi anemia".   An excerpt from the abstract, "Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2."  See this press release on the discovery. The gene is also known as "POG".

FANCM Gene

Comments - also called FAAP250.

Read about the discovery here:
A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M, by Meetei et al; Nature Genetics 37, 958-963 (2005). Published online 21 August 2005.

Back to Genetics of Fanconi Anemia

Last updated: 01 Sep 2005