Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 604460

FAS-ASSOCIATED FACTOR 1; FAF1

Alternative titles; symbols

HFAF1

HGNC Approved Gene Symbol: FAF1

Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38) : 1:50,437,028-50,960,267 (from NCBI)

TEXT

Cloning and Expression

Interaction of Fas ligand (TNFSF6; 134638) with FAS antigen (TNFRSF6; 134637) mediates programmed cell death, also called apoptosis, in a number of organ systems, notably the immune and nervous systems. Although these molecules are in the same family as TNF-alpha (191160) and TNFR (191190), the latter function to activate not only apoptosis but also NFKB1 (164011), a key transcription factor in chronic inflammatory diseases. By screening tumor-related proteins derived from a HeLa cDNA library in a yeast 2-hybrid assay, Ryu et al. (1999) isolated a truncated version of FAF1, which could enhance but not initiate apoptosis. Using PCR as well as sequence information from an EST database to screen HeLa as well as brain and kidney cDNA libraries, they derived a product corresponding to the expected size of the complete coding region of 1,970 bp. The deduced 650-amino acid protein has 2 ubiquitin homology domains (UB1 and UB2) near the N terminus, followed by a nuclear localization signal, a region of homology with chromatin assembly factor p150 (CHAF1A; 601246), and a C-terminal domain showing homology with proteins involved in ubiquitination. The human protein is 96% and 85% homologous to mouse and quail Faf1, respectively. Northern blot analysis revealed a single FAF1 mRNA transcript of 2.8 kb that was most abundant in testis, slightly less abundant in skeletal muscle and heart, followed by prostate, thymus, ovary, small intestine, and colon. Expression was detected in all other tissues tested with the exception of peripheral blood leukocytes. By immunoblotting with a mouse polyclonal antibody to FAF1, a 74-kD protein was detected in 6 of 8 tumor cell lines. A 40-kD protein was detected in 1 of the 2 remaining cell lines.

Using whole-mount in-situ hybridization in zebrafish embryos, Ghassibe-Sabbagh et al. (2011) detected faf1 transcripts at 24 and 30 hours postfertilization (hpf) in the pharyngeal arch primordia. At 56 hpf, when the pharyngeal cartilages were forming, faf1 was strongly expressed in all arches, with the most prominent expression in the first (mandibular) and second (hyoid) arch. Knockdown of zebrafish faf1 led to pharyngeal cartilage defects and jaw abnormalities as a result of a failure of the cranial neural crest to differentiate and to express cartilage-specific markers, such as sox9a (see 608160) and col2a1 (see 120140). Administration of faf1 mRNA rescued the phenotype.

Gene Function

Ryu et al. (1999) showed that FAF1 and FAS interacted in both yeast 2-hybrid and GST pull-down assay systems. The N-terminal 201 amino acids of FAF1, containing the UB1 domain, bound to the FAS death domain, but not to a death domain mutant, in the yeast 2-hybrid system.

Using immunoprecipitation and protein pull-down assays, Sul et al. (2013) found that FAF1 interacted with the E3 ubiquitin ligase parkin (PARK2; 602544) in SH-SY5Y human neuroblastoma cells. Deletion analysis revealed that the UB1 domain of FAF1 and the N-terminal half of parkin, which includes a ubiquitin-like domain and a RING1 domain, were required for the interaction. Parkin overexpression significantly increased ubiquitination of FAF1. Parkin used UBCH7 (UBE2L3; 603721) as the E2 ubiquitin-conjugating enzyme for lys48-linked ubiquitination of FAF1, which targeted FAF1 for proteasomal degradation. Exposure of SH-SY5Y cells to Parkinson disease (PD; see 168600)-inducing neurotoxin 1-methyl-4-phenylpyridinium caused FAF1-dependent cell death via JNK1 (MAPK8; 601158) and caspase-3 (CASP3; 600636) activation and generation of reactive oxygen species. Coexpression of wildtype parkin attenuated the cellular effects of FAF1 in a dose-dependent manner.

Mapping

Gross (2011) mapped the FAF1 gene to chromosome 1p32.3 based on an alignment of the FAF1 sequence (GenBank AF136173) with the genomic sequence (GRCh37).

Molecular Genetics

For discussion of a possible association between variation in the FAF1 gene and orofacial clefting, see OFC13 (613857).

Animal Model

Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces PD-like pathology in mice. Sul et al. (2013) found that Faf1 expression accumulated in the ventral midbrain of MPTP-treated PD model mice. Faf1 expression was also elevated in the ventral midbrain of parkin -/- mice and in parkin -/- mouse embryonic fibroblasts. Knockdown of Faf1 via gene trap insertion into Faf1 intron 8 generated a hypomorphic allele (gt) that allowed mice to survive and protected Faf1 gt/gt mice from MPTP-induced dopaminergic neuronal loss. Faf1 gt/gt mice were also protected from locomotor defects found in MPTP-treated PD model mice. Sul et al. (2013) noted that FAF1 is upregulated in PD patients, and they hypothesized that FAF1 may contribute to PD through deregulation of ubiquitin-mediated protein degradation.

REFERENCES

  1. Ghassibe-Sabbagh, M., Desmyter, L., Langenberg, T., Claes, F., Boute, O., Bayet, B., Pellerin, P., Hermans, K., Backx, L., Mansilla, M. A., Imoehl, S., Nowak, S., and 17 others.FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish. Am. J. Hum. Genet. 88: 150-161, 2011. [PubMed: 21295280] [Full Text: https://doi.org/10.1016/j.ajhg.2011.01.003\]
  2. Gross, M. B.Personal Communication. Baltimore, Md. 4/1/2011.
  3. Ryu, S. W., Chae, S. K., Lee, K. J., Kim, E.Identification and characterization of human Fas associated factor 1, hFAF1. Biochem. Biophys. Res. Commun. 262: 388-394, 1999. [PubMed: 10462485] [Full Text: https://doi.org/10.1006/bbrc.1999.1217\]
  4. Sul, J.-W., Park, M.-Y., Shin, J., Kim, Y.-R., Yoo, S.-E., Kong, Y.-Y., Kwon, K.-S., Lee, Y. H., Kim, E.Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration. Hum. Molec. Genet. 22: 1558-1573, 2013. [PubMed: 23307929] [Full Text: https://doi.org/10.1093/hmg/ddt006\]

Contributors:

Patricia A. Hartz - updated : 4/17/2014
Matthew B. Gross - updated : 4/1/2011
Marla J. F. O'Neill - updated : 4/1/2011

Creation Date:

Paul J. Converse : 1/24/2000

Edit History:

mgross : 04/17/2014
mgross : 4/17/2014
mcolton : 4/8/2014
carol : 4/1/2011
carol : 4/1/2011
carol : 1/24/2000