4q35.2

CDHF7,CDHR8,FAT,ME5,hFat1

Various cancers

FAT1, a member of the cadherin gene family, is homologue of Drosophila tumour suppressor gene fat. In Drosophila, fat gene is important in controlling cell proliferation during development and any defect in the expression of fat would lead to tumor development (Bryant et al., 1988). Dunne et al. (1995) have identified the human homologue and studied the tissue distribution of FAT transcripts in adult and fetal tissues.
Loss of heterozygosity and altered expression of FAT1 has been found in human glial tumors (Chosdol et al., 2009). Homozygous deletion of FAT1 gene was detected in oral cancer (Nakaya et al., 2007). Kwaepila et al. (2006) found higher FAT1 expression in more malignant form of breast cancer tissues by immunohistochemistry (IHC). There are studies showing LOH and/or deletion of the chromosome 4q34-35 region (which harbors FAT gene) in many tumors including gliomas. LOH was found in grade IV gliomas using microsatellite markers (Hu et al., 2002), though the gene itself has not been implicated. Other tumors like small cell lung carcinoma (Cho et al., 2002), hepatocellular carcinoma (Zhang et al., 2005; Chang et al., 2002) and cervical carcinoma (Backsch et al., 2005) etc showed alterations/LOH in the chromosomal 4q34-q35 locus and significant association of 4q34-q35 region with increased risk of progression of these tumors was suggested. Since the FAT gene is located in this region it may have an important role to play in the development and progression of these tumors.

Astrocytic tumour

Loss of heterozygosity and altered expression of FAT1 in astrocytic tumors (Chosdol et al., 2009).

Breast cancer

Increased FAT1 expression contributes to loss of duct formation, and increased cell migration and invasion in breast cancer (Kwaepila et al., 2006).

Oral cancer

Homozygous deletion of FAT in the cell lines and in primary oral cancers was studied. Homozygous deletion hot spots were observed in exon 1 (9/20, 45%) and exon 4 (7/20, 35%). The methylation status of the FAT CpG island in squamous cell carcinomas correlated negatively with its expression. Mutations in FAT is suggested as an important factor in the development of oral cancer. Moreover, loss of gene expression was identified in other types of squamous cell carcinoma (Nakaya et al., 2007).

Psychiatric disorders

Bipolar disorder: a positional cloning strategy, combined with association analysis have provided evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder (Blair et al., 2006).

Cell migration

FAT1 is known to play role in cell migration. FAT1 knockdown decreases cell migration in vascular smooth muscle cells (Hou et al., 2006; Hou and Sibinga, 2009). FAT1 plays an integrative role in regulating cell migration by participating in Ena/VASP-dependent regulation of cytoskeletal dynamics (Moeller et al., 2004).