Alternative titles; symbols
HGNC Approved Gene Symbol: FAT1
Cytogenetic location: 4q35.2 Genomic coordinates (GRCh38): 4:186,587,794-186,726,696 (from NCBI)
The FAT1 gene encodes a member of a small family of vertebrate cadherin-like genes whose gene products play a role in cell migration, lamellipodia dynamics, cell polarity, and cell-cell adhesions (summary by Gee et al., 2016).
The Drosophila 'fat' gene does not belong to the classical cadherin gene family (see CDH1; 192090) yet encodes a transmembrane protein containing 34 cadherin repeats in association with a number of other motifs Mahoney et al. (1991). The Drosophila 'fat' locus encodes a tumor suppressor gene, and recessive (loss-of-function) mutations lead to hyperplastic overgrowth of the imaginal discs, indicating that contact-dependent cell interactions may play an important role in regulating growth (Bryant et al., 1988). This excessive cell proliferation occurs while maintaining normal epithelial organization and differentiation potential. Dunne et al. (1995) reported the sequence of a cDNA that was serendipitously obtained during a screen of a human T-lymphocyte cDNA library. The full-length cDNA had the potential to encode a large protein that most resembled the Drosophila 'fat' protein in its possession of 34 cadherin repeats and other characteristics. Therefore, they named the gene and the gene product FAT. Analysis of the expression of FAT in fetal and adult tissues revealed that FAT mRNA is present in many epithelial and some endothelial and smooth muscle cells. The authors commented that the molecule is probably important in mammalian developmental processes and cell communication. The large FAT protein was predicted to contain nearly 4600 residues.
Katoh and Katoh (2006) determined that full-length FAT1 has 33 cadherin repeats, a laminin G (see LAMC1; 150290) domain, and 2 EGF (131530) domains in its extracellular region, followed by a transmembrane region and a C-terminal cytoplasmic domain containing a PDZ-binding motif. In silico analysis identified FAT1 mRNAs in embryonic stem cells, neural tissues, and a variety of tumors.
Caruso et al. (2013) stated that the cytoplasmic domain of human FAT1 can translocate to the nucleus. Database analysis identified possible variants of mouse and human FAT1 that initiate from alternative downstream promoters, and some encode isoforms predicted to lack transmembrane domains. Immunohistochemical analysis of adult mouse skeletal muscle fibers detected Fat1 in stripes that closely juxtaposed with Dhpr (see CACNA1S, 114208), a calcium channel of transverse tubules. Fat1 was also detected in myofiber nuclei.
Cell-cell interactions that involve adhesion molecules are important in many developmental processes. Dunne et al. (1995) stated that many adhesion molecules have been found to be conserved between Drosophila and vertebrates, indicating that the adhesion molecules involved in tissue morphogenesis evolved long before the divergence of the arthropods and chordates (Hortsch and Goodman, 1991). Adhesion molecules have been classified into 4 major families: the immunoglobulin superfamily, the integrin superfamily, the selectin family, and the cadherin superfamily. Cadherins mediate homophilic, calcium-dependent cell-cell adhesion in a wide variety of tissues and are important regulators of morphogenesis, and loss of function may be involved in the invasion and metastasis of malignant tumors. The original or classical adherins have a highly conserved domain structure typically including 5 extracellular, conserved repeated amino acid sequences (cadherin repeats).
Katoh and Katoh (2006) identified a TCF/LEF (see LEF1; 153245)-binding site within the 5-prime promoter region of the FAT1 gene.
Dunne et al. (1995) localized the FAT1 gene to chromosome 4q34-q35 by isotopic in situ hybridization.
By genomic sequence analysis, Katoh and Katoh (2006) mapped the FAT1 gene to chromosome 4q35.2, where it is linked with the MTNR1A gene (600665). The FAT1-MTNR1A locus on chromosome 4 is paralogous to the FAT3 (612483)-MTNR1B (600804) locus on chromosome 11.
The atypical cadherin Fat acts as a receptor for a signaling pathway that regulates growth, gene expression, and planar cell polarity. Genetic studies in Drosophila identified the 'four-jointed' (Fj) gene (612206) as a regulator of Fat signaling. Ishikawa et al. (2008) showed that Four-jointed encodes a protein kinase that phosphorylates serine or threonine residues within extracellular cadherin domains of Fat and its transmembrane ligand, Dachsous (see 603057). Four-jointed functions in the Golgi and was the first molecularly defined kinase that phosphorylates protein domains destined to be extracellular. An acidic sequence motif (Asp-Asn-Glu) within Four-jointed was essential for its kinase activity in vitro and for its biologic activity in vivo. Ishikawa et al. (2008) concluded that Four-jointed regulates Fat signaling by phosphorylating cadherin domains of Fat and Dachsous as they transit through the Golgi.
Cao et al. (2016) demonstrated that the atypical Fat1 cadherin acts as a molecular 'brake' on mitochondrial respiration that regulates vascular smooth muscle cell (SMC) proliferation after arterial injury. Fragments of Fat1 accumulate in SMC mitochondria, and the Fat1 intracellular domain interacts with multiple mitochondrial proteins, including critical factors associated with the inner mitochondrial membrane. SMCs lacking Fat1 (Fat1KO) grow faster, consume more oxygen for ATP production, and contain more aspartate. Notably, expression in Fat1KO cells of a modified Fat1 intracellular domain that localizes exclusively to mitochondria largely normalizes oxygen consumption, and the growth advantage of these cells can be suppressed by inhibition of mitochondrial respiration, which suggest that a Fat1-mediated growth control mechanism is intrinsic to mitochondria. Consistent with this idea, Fat1 species associate with multiple respiratory complexes, and Fat1 deletion both increases the activity of complexes I and II and promotes the formation of complex I-containing supercomplexes. In vivo, Fat1 is expressed in injured human and mouse arteries, and inactivation of SMC Fat1 in mice potentiates the response to vascular damage, with markedly increased medial hyperplasia and neointimal growth, and evidence of higher SMC mitochondrial respiration. Cao et al. (2016) concluded that their studies suggested that Fat1 controls mitochondrial activity to restrain cell growth during the reparative, proliferative state induced by vascular injury.
Using yeast 2-hybrid screening and deletion analysis, de Bock et al. (2017) showed that SH3RF1 (618642) interacted with FAT1 through its 2 N-terminal SH3 domains. Knockdown of SH3RF1 in human breast cancer cells resulted in significant upregulation of FAT1 protein levels and increased cell surface expression of FAT1, with no obvious change in processing of full-length FAT1 to its cleaved form. In contrast, overexpression of SH3RF1 resulted in a 30% reduction in FAT1 protein levels. Deletion analysis revealed that the RING domain of SH3RF1 was essential for regulating FAT1 levels. Further analysis demonstrated that SH3RF1 did not regulate cleavage of FAT1 or influence the rate of FAT1 protein turnover.
Somatic FAT1 Mutations in Cancer
Morris et al. (2013) reported recurrent somatic mutations in FAT1 in glioblastoma (8 of 39; 20.5%), colorectal cancer (3 of 39; 7.7%), and head and neck cancer (4 of 60; 6.7%). FAT1 encodes a cadherin-like protein, which was able to potently suppress cancer cell growth in vitro and in vivo by binding beta-catenin (116806) and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival. Morris et al. (2013) concluded that the data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis.
Associations Pending Confirmation
For a possible association between nephrotic syndrome (see, e.g., NPHS1, 256300) and variation in the FAT1 gene, see 600976.0001.
Puppo et al. (2015) identified heterozygous missense variants in the FAT1 gene in 10 of 49 unrelated Japanese patients with a neuromuscular phenotype similar to facioscapulohumeral muscular dystrophy (see, e.g., FSHD1, 158900). None of the patients had contractions or hypomethylation at the D4Z4 region (see 606009), indicating that they did not have epigenetic changes at the 4q35 region, and none had variants in the SMCHD1 gene (614982). Seven of the 10 variants were annotated in the dbSNP (build 137) database. Although all variants were missense, all were predicted to affect splicing of the FAT1 gene, possibly resulting in functionally aberrant proteins. However, only 4 of the variants could be tested in vitro and were demonstrated to result in aberrant splicing. The findings suggested that defective FAT1 may be associated with an FSHD-like phenotype. Puppo et al. (2015) chose FAT1 as a candidate gene based on the findings of Caruso et al. (2013) that hypomorphic Fat1 mice have an FSHD-like phenotype (see ANIMAL MODEL). Caruso et al. (2013) showed that mouse Fat1 was involved in muscle patterning by modulating the polarity of myoblast migration during embryonic development.
Ciani et al. (2003) found that Fat1-null mice showed perinatal lethality, most likely caused by renal failure due to loss of the renal glomerular slit junctions and fusion of glomerular epithelial foot processes. Renal histology was normal, and the defects were apparent on electron microscopy. In contrast, epithelial intercellular adhesion complexes in the mouse skin and lungs were normal on electron microscopy. A small percentage of mutant mice also showed defects in forebrain development, including holoprosencephaly, and eye development, including microphthalmia, with evidence of apoptosis. There was no evidence of proliferation abnormalities in the 2 tissues examined, skin and central nervous system, leading Ciani et al. (2003) to conclude that there are significant functional differences between Drosophila fat1, which acts as a tumor suppressor gene, and vertebral Fat1.
Caruso et al. (2013) found that mice homozygous for a hypomorphic Fat1 allele showed retinal vasculopathy, features of polycystic kidneys, and postural abnormalities, including scapular winging and kyphosis, without skeletal abnormalities. Some skeletal muscles, including trapezius, rhomboid, pectoralis major, latissimus dorsi, and cutaneous maximus, showed necrosis and inflammatory infiltrations. A proportion of these showed neuromuscular junction fragmentation. Mutant embryos showed dispersed myocytes, ectopic muscle, and reduced myofiber density in cutaneous maximus. Caruso et al. (2013) hypothesized that FAT1 has a role in determining polarity of myoblast migration.
Gee et al. (2016) found that mice with podocyte-specific loss of Fat1 did not show embryonic lethality and had normal renal histology. However, electron microscopy showed persistence of cuboidal podocytes, wide foot processes, and abnormal slit diaphragms. Adult mutant mice developed progressive proteinuria, focal segmental glomerulosclerosis, and tubulointerstitial nephropathy. Morpholino knockdown of fat1 in zebrafish embryos resulted in the development of pronephric cysts in 24% of animals; rac1 (602048) and cdc42 (116952) activation mitigated the defects.
This variant is classified as a variant of unknown significance because its contribution to nephrotic syndrome (see, e.g., NPHS1, 256300) has not been confirmed.
In a 15-year-old Turkish boy (patient A4623), born of consanguineous parents, with steroid-resistant nephrotic syndrome (SRNS), Gee et al. (2016) identified a homozygous 4-bp deletion (c.3093_3096del) in exon 2 of the FAT1 gene, resulting in a frameshift and premature termination (Pro1032CysfsTer11). The variant, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 137) or Exome Variant Server databases. The patient also carried rare variants in the PIDD (605247) and DZIP1 (608671) genes. Mutations in 27 known SRNS genes were excluded. In addition to nephrotic syndrome with hematuria and renal tubular ectasia, the patient had intellectual disability, blepharoptosis, pulmonary artery stenosis, pachygyria, and Virchow-Robin spaces on brain imaging. Renal biopsy showed effacement of the glomerular podocyte foot processes, tubulointerstitial infiltrations, and irregular tubular basement membranes. Patient fibroblasts showed absence of the FAT1 protein and decreased migration rates compared to controls. Knockdown of FAT1 in differentiated podocytes showed similarly decreased migration rates, which were associated with decreased active RAC1 (602048) and CDC42 (116952), implicating a defect in RHO GTPase signaling in the pathogenesis. Accordingly, the migration defects in patient fibroblasts and podocytes were partially rescued by activation of RAC1/CDC42. Mutant fibroblasts and FAT1-silenced podocytes also showed impaired cell-cell adhesion.
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Puppo, F., Dionnet, E., Gaillard, M.-C., Gaildrat, P., Castro, C., Vovan, C., Bertaux, K., Bernard, R., Attarian, S., Goto, K., Nichino, I., Hayashi, Y., Magdinier, F., Krahn, M., Helmbacher, F., Bartoli, M., Levy, N. Identification of variants in the 4q35 gene FAT1 inpatients with a facioscapulohumeral dystrophy-like phenotype. Hum. Mutat. 36: 443-453, 2015. [PubMed: 25615407] [Full Text: https://doi.org/10.1002/humu.22760]