Alternative titles; symbols
HGNC Approved Gene Symbol: FAN1
SNOMEDCT: 782738008;
Cytogenetic location: 15q13.3 Genomic coordinates (GRCh38): 15:30,903,852-30,943,108 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q13.3 | Interstitial nephritis, karyomegalic | 614817 | Autosomal recessive | 3 |
FAN1 is a DNA endo- and exonuclease involved in the repair of DNA damage caused by crosslinking agents. FAN1 is recruited to sites of interstrand crosslink damage by interacting with the FANCI (611360)-FANCD2 (227646) complex (MacKay et al., 2010; Kratz et al., 2010; Smogorzewska et al., 2010).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned FAN1, which they designated KIAA1018. The deduced protein contains 1,017 amino acids. RT-PCR analysis detected relatively uniform FAN1 expression in all adult and fetal tissues and specific adult brain regions examined.
Kratz et al. (2010) stated that the FAN1 protein contains a predicted N-terminal RAD18 (605256)-like ubiquitin (191339)-binding zinc finger domain and a C-terminal nuclease domain.
Zhou et al. (2012) found expression of the FAN1 gene in multiple parenchymatous human tissues, including the kidney, liver, neuronal tissue, and female reproductive organs. The expression pattern differed from that of FANCD2, which was found primarily in lymphatic and bone marrow-derived sources, as well as in skin and testes.
Using tandem affinity purification and large-scale immunoprecipitation analysis, followed by mass spectroscopy, Cannavo et al. (2007) identified FAN1 as a protein that interacted with the mismatch repair proteins MLH1 (120436), PMS1 (600258), and PMS2 (600259).
Independently, MacKay et al. (2010) and Kratz et al. (2010) found that recombinant human FAN1 exhibited DNA endonuclease activity toward 5-prime flaps and had 5-prime exonuclease activity mediated by its C-terminal nuclease domain. Only DNA damage caused by interstrand crosslinking agents resulted in recruitment of FAN1 to sites of DNA damage, and this recruitment required interaction of FAN1 with monoubiquitinated FANCD2. Depletion of FAN1 sensitized human cell lines to interstrand crosslinking agents and caused chromosomal instability. Smogorzewska et al. (2010) reported similar findings and showed that FAN1 required both FANCI and FANCD2 (613984) for localization at sites of DNA damage.
A central event in the Fanconi pathway is monoubiquitylation of the FANCI-FANCD2 protein complex. Liu et al. (2010) characterized FAN1, which promotes interstrand crosslink repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on monoubiquitylation of the FANCI-FANCD2 complex. Liu et al. (2010) concluded that the monoubiquitylated complex recruits the downstream repair protein FAN1 and facilitates repair of DNA interstrand crosslinks.
Yoshikiyo et al. (2010) found that recombinant chicken Fan1 functioned as an endonuclease that mostly shared substrate specificity with its human ortholog. Fan1 also had a 5-prime-to-3-prime exonuclease activity that preferred double-stranded DNA ends. Knockout of Fan1 in chicken DT40 cells did not affect growth, but the cells became more sensitive to interstrand crosslink-inducing agents. Loss of Fan1 resulted in chromosomal instability quantitatively comparable to that seen in Fanconi anemia (FA) cells. Fan1 was not involved in processing of spontaneous DNA damage with FA proteins, as FA and Fan1 deficiencies were additive rather than epistatic. Unlike FA cells, Fan1 deficiency in DT40 cells did not affect ubiquitylation of Fancd2. Fan1 and Fancd2 colocalized and were targeted to the same foci, and this targeting depended on a functional FA complex.
Using a series of mutant Fan1 and Fancd2 constructs with wildtype and mutant mouse embryonic fibroblasts, Lachaud et al. (2016) found that the nuclease activity of Fan1, but not its interaction with ubiquitinated Fancd2, was required for Fan1-dependent repair of DNA interstrand crosslinks. However, both its nuclease activity and its interaction with ubiquitinated Fancd2 were required for Fan1 to restrain stalled forks in DNA and prevent subsequent chromosome abnormalities.
In a transcriptomewide association study, Goold et al. (2019) found that FAN1 expression was associated with slower Huntington disease (HD; 143100) progression and delayed age at onset. Expression of FAN1 in FAN1 -/- U2OS osteosarcoma cells increased the length-dependent stability of the CAG repeat in the huntingtin (HTT; 613004) gene. The nuclease domain of FAN1 was not required to stabilize the HTT CAG repeat in U2OS cells. FAN1 protected against expansion of the endogenous HTT CAG repeat, as knockout of FAN1 increased the expansion rate. FAN1 bound to the HTT CAG repeat, and the binding was not length specific. Moreover, CAG repeat binding by FAN1 was not specific to the HTT gene.
Crystal Structure
Using FAN1 DNA crystal structures and biochemical data, Wang et al. (2014) found that human FAN1 cleaves DNA successively at every third nucleotide in a DNA interstrand crosslink. In vitro, this exonuclease mechanism allows FAN1 to excise an interstrand crosslink from 1 strand through flanking incisions. DNA access requires a 5-prime terminal phosphate anchor at a nick or a 1- or 2-nucleotide flap and is augmented by a 3-prime flap, suggesting that FAN1 action is coupled to DNA synthesis or recombination. Wang et al. (2014) suggested that FAN1's mechanism of interstrand crosslink excision is well suited for processing other localized DNA adducts as well.
Using radiation hybrid analysis, Nagase et al. (1999) mapped the FAN1 gene to chromosome 15.
Stumpf (2021) mapped the FAN1 gene to chromosome 15q13.3 based on an alignment of the FAN1 sequence (GenBank BC047882) with the genomic sequence (GRCh38).
In affected members of 9 unrelated families with karyomegalic interstitial nephritis (KMIN; 614817), Zhou et al. (2012) identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene (see, e.g., 613534.0001-613534.0008). Eight of the 12 mutations resulted in a truncated protein. The first mutation was identified by homozygosity mapping and exome sequencing in 1 affected family. Upon exposure to mitomycin C, FAN1 mutant cells showed genomic instability, as manifest by increased chromatid breaks and radial chromosomes on metaphase spreads. Although the results of the test for Fanconi anemia (see, e.g., 227650), diepoxybutane-induced breakage, were negative in FAN1-mutant cells lines, these cells still showed decreased survival in response to either inducer of interstrand crosslink repair (ICL) compared to controls. Thus, there were subtle differences in cell reaction between FANCA (607139)-mutant and FAN1-mutant cells, suggesting that these proteins act in somewhat distinct manners. None of the FAN1 mutant proteins was able to correct mitomycin C-induced decreased survival in cells lacking FAN1 nuclease activity. Morpholino knockdown of Fan1 in zebrafish embryos resulted in a nephronophthisis (NPHP; 256100)-like phenotype, with shortened and curved body axis, as well as a Fanconi anemia-like phenotype, with microcephaly, microphthalmia, and massive apoptosis. There was evidence of activation of the DNA damage repair pathway, as demonstrated by increased signaling for gamma-H2AX (H2AFX; 601772). Knockdown of born Fan1 and p53 (191170) in zebrafish caused renal cysts, reminiscent of a ciliopathy. In the fawn-hooded hypertensive rat, an animal model of chronic kidney disease, as well as in kidney samples from humans with genetically heterogeneous forms of chronic kidney disease, Zhou et al. (2012) found increased nuclear staining for gamma-H2AX, indicating activation of the DNA damage response pathway. These findings supported the hypothesis that DNA lesions and DNA damage response pathways may partially drive renal damage in NPHP-related ciliopathies and in chronic kidney disease.
Associations Pending Confirmation
For discussion of a possible association between variation in the FAN1 gene and colorectal cancer, see 114500.
Lachaud et al. (2016) found that homozygous transgenic mice expressing a nuclease-dead (nd) Fan1, but not wildtype controls, developed tumors by 20 month of age. The majority of tumors in Fan1(nd/nd) mice were pulmonary carcinomas or hepatic lymphomas.
In 2 brothers of Maori descent with karyomegalic interstitial nephritis (KMIN; 614817) (Palmer et al., 2007), Zhou et al. (2012) identified a homozygous 2120G-A transition in exon 8 of the FAN1 gene, resulting in a trp707-to-ter (W707X) substitution. The mutation was found by homozygosity mapping and exome sequencing of the candidate region. The mutation was not found in 96 controls.
In affected members of 2 French families with karyomegalic interstitial nephritis (KMIN; 614817), Zhou et al. (2012) identified compound heterozygosity for 2 mutations in the FAN1 gene. Both families carried a T-to-A transition in intron 2 (1234+2T-A), resulting in a splice site mutation on 1 allele. One family (Godin et al., 1996) carried a 2-bp deletion in exon 7 (2036_2037delGA; 613534.0003) on the second allele, and the other family carried a 2245C-T transition in exon 9, resulting in an arg749-to-ter (R749X; 613534.0004) substitution on the second allele. None of the mutations were found in 96 controls, and haplotype analysis suggested a founder effect for the splice site mutation.
For discussion of the 2-bp deletion in the FAN1 gene (2036_2037delGA) that was found in compound heterozygous state in affected members of a family with karyomegalic interstitial nephritis (KMIN; 614817) by Zhou et al. (2012), see 613534.0002.
For discussion of the arg749-to-ter mutation (R749X) in the FAN1 gene that was found in compound heterozygous state in affected members of a family with karyomegalic interstitial nephritis (KMIN; 614817) by Zhou et al. (2012), see 613534.0002.
In a woman of Spanish descent with karyomegalic interstitial nephritis (KMIN; 614817) originally reported by Spoendlin et al. (1995), Zhou et al. (2012) identified a homozygous 1-bp deletion (2616delA) in exon 12 of the FAN1 gene, resulting in a frameshift and premature termination (Asp873ThrfsTer17). An unrelated woman of French descent (Verine et al., 2010) was compound heterozygous for 2616delA and a G-to-A transition in intron 3 (1375+1G-A), resulting in a splice site mutation (613534.0006). Neither mutation was found in 96 controls.
For discussion of the splice site mutation in the FAN1 gene (1375+1G-A) that was found in compound heterozygous state in a patient with karyomegalic interstitial nephritis (KMIN; 614817) by Zhou et al. (2012), see 613534.0005.
In a patient with karyomegalic interstitial nephritis (KMIN; 614817) originally reported by Baba et al. (2006), Zhou et al. (2012) identified compound heterozygosity for 2 mutations in the FAN1 gene: a 2-bp deletion (2774_2775delTT) in exon 12, resulting in a frameshift and premature termination (Leu925ProfsTer25), and a 2810G-A transition in exon 13, resulting in a gly937-to-asp (G937D; 613534.0008) substitution at a highly conserved residue. Neither mutation was found in 96 controls.
For discussion of the gly937-to-asp (G937D) mutation in the FAN1 gene that was found in compound heterozygous state in a patient with karyomegalic interstitial nephritis (KMIN; 613534.0007) by Zhou et al. (2012), see 613534.0007.
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