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FAT ATYPICAL CADHERIN 4; FAT4

FAT ATYPICAL CADHERIN 4; FAT4

Alternative titles; symbolsFAT TUMOR SUPPRESSOR, DROSOPHILA, HOMOLOG OF, 4FATJHGNC Approved Gene Symbol: FAT4Cytogenetic location: 4q28.1 Genomic coordinates...

Alternative titles; symbols

  • FAT TUMOR SUPPRESSOR, DROSOPHILA, HOMOLOG OF, 4
  • FATJ

HGNC Approved Gene Symbol: FAT4

Cytogenetic location: 4q28.1 Genomic coordinates (GRCh38): 4:125,314,917-125,492,931 (from NCBI)

▼ Description
The FAT4 gene encodes a protein that is a member of a large family of protocadherins. DCHS1 (603057) is another protocadherin that is the ligand for FAT4; FAT4 and DCHS1 form an apically located adhesive complex in the developing brain (summary by Cappello et al., 2013).

▼ Cloning and Expression
By searching databases using a cadherin motif, Hoeng et al. (2004) identified human FAT4, which they called FATJ. The deduced 3,222-amino acid protein contains a long N-terminal cadherin (see CDH1; 192090) ectodomain, followed by a flamingo box, 3 EGF (131530) domains, 2 laminin G (see LAMC1, 150290) domains, a fourth EGF domain, a transmembrane domain, and a C-terminal tail. PCR analysis detected FAT4 expression in all human tissues examined except skeletal muscle and peripheral blood leukocytes.

Katoh and Katoh (2006) determined that full-length FAT4 encodes a deduced 4,924-amino acid protein with 34 extracellular cadherin repeats. In silico analysis identified FAT4 mRNAs in fetal brain, infant brain, brain tumor, and colorectal cancer. Phylogenetic analysis revealed that FAT4 is divergent from FAT1 (600976), FAT2 (604269), and FAT3 (612483).

Cappello et al. (2013) found strong expression of the FAT4 gene in the apical neuroepithelium of 9-week-old human embryos. There was weaker staining in the subventricular zone and within the cortical plate.

▼ Gene Function
In experiments in mice, Saburi et al. (2008) demonstrated that Fat4 is an essential gene that has a key role in vertebrate planar cell polarity (PCP). Loss of Fat4 disturbed oriented cell divisions and tubule elongation during kidney development, leading to cystic kidney disease. Fat4 genetically interacts with the PCP genes Vangl2 (600533) and Fjx1 (612206) in cyst formation. In addition, Fat4 represses Fjx1 expression, indicating that signaling is conserved. Saburi et al. (2008) concluded that, taken together, their data suggested that FAT4 regulates vertebrate PCP and that loss of PCP signaling may underlie some cystic diseases in humans.

▼ Gene Structure
Hoeng et al. (2004) determined that the FAT4 gene contains 15 exons and spans 36 kb. Katoh and Katoh (2006) determined that the first exon of the FAT4 gene is noncoding.

▼ Mapping
By genomic sequence analysis, Hoeng et al. (2004) mapped the FAT4 gene to chromosome 4q28.1.

▼ Molecular Genetics
Van Maldergem Syndrome 2

In 5 patients from 4 unrelated families with Van Maldergem syndrome-2 (VMLDS2; 601390), Cappello et al. (2013) identified biallelic mutations in the FAT4 gene (612411.0001-612411.0006). The first mutations were found by whole-exome sequencing, and the subsequent mutations were found by whole-exome sequencing or targeted Sanger sequencing. All mutations segregated with the disorder in the families. Functional studies were not performed, but animal studies suggested that loss of Fat4 resulted in defects of neocortical development similar to those observed in the patients. Two of the patients had been reported by Mansour et al. (2012) and 1 by Neuhann et al. (2012). Clinical features included characteristic dysmorphic facies, tracheomalacia, microtia, intellectual disability, and skeletal dysplasia. Brain MRI showed periventricular nodular heterotopia.

Hennekam Lymphangiectasia-Lymphedema Syndrome 2

In affected members of 5 unrelated families with Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006), Alders et al. (2014) identified homozygous or compound heterozygous mutations in the FAT4 gene (see, e.g., 612411.0007-612411.0010). The mutation in the first family was found by whole-exome sequencing. Subsequent mutations were identified in 4 of 24 Hennekam syndrome patients who underwent direct sequencing of the FAT4 gene. Overall, FAT4 mutations were present in 5 (20%) of 25 families with the disorder. One of the homozygous mutations (E2375K; 612411.0003) had previously been reported by Cappello et al. (2013) in compound heterozygosity with a truncating mutation in a patient with Van Maldergem syndrome-2. Functional studies of the FAT4 variants were not performed.

▼ Animal Model
Cappello et al. (2013) found that Fat4-null and Dchs1-null embryonic mice had no evidence of a malformation of cortical development at days E16 and E18. Postnatal examination was precluded by the lethality of both genotypes. These findings indicated a discordance between the human and mice knockout models. However, intraventricular electroporation of shRNAs against Fat4 and Dchs1 in mouse embryos showed that the electroporated cells accumulated in the proliferative zones of the developing cortex, with significantly fewer cells reaching the cortical plate in the knockdown embryos compared to controls. This was observed also at later stages (P7), when many electroporated cells failed to migrate to the upper layers or accumulated below the gray matter, forming distinct regions of neuronal heterotopia that were reminiscent of the periventricular neuronal heterotopia phenotype in human patients with mutations in these genes. Immunostaining studies indicated increased proliferation of the cells in the ventricular and subventricular zones as well as a decrease in neuronal cell differentiation. These effects were countered by concurrent knockdown of Yap (606608), a transcriptional effector of the Hippo signaling pathway. These findings implicated Dchs1 and Fat4 upstream of Yap as key regulators of mammalian neurogenesis.

▼ ALLELIC VARIANTS ( 10 Selected Examples):

.0001 VAN MALDERGEM SYNDROME 2
FAT4, CYS4159PHE
In a patient (F1) with Van Maldergem syndrome-2 (VMLDS2; 615546), Cappello et al. (2013) identified compound heterozygous mutations in the FAT4 gene: a c.12476G-T transversion in exon 14, resulting in a cys4159-to-phe (C4159F) substitution, and a c.13193G-A transition in exon 17, resulting in a cys4398-to-tyr (C4398Y; 612411.0002) substitution. Both substitutions occurred at highly conserved residues in the LAM-G-like domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. They were not found in the dbSNP or 1000 Genomes Project databases. Cys4159 and Cys4398 mediate the formation of disulfide bonds proposed to contribute to structural orientation of adjacent domains. The patient had previously been reported as patient 1 by Mansour et al. (2012).

.0002 VAN MALDERGEM SYNDROME 2
FAT4, CYS4398TYR
For discussion of the cys4398-to-tyr (C4398Y) mutation in the FAT4 gene that was found in compound heterozygous state in a patient with Van Maldergem syndrome-2 (VMLDS2; 615546) by Cappello et al. (2013), see 612411.0001.

.0003 VAN MALDERGEM SYNDROME 2
HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2, INCLUDED
FAT4, GLU2375LYS
Van Maldergem Syndrome 2

In a patient (F2) with Van Maldergem syndrome-2 (VMLDS2; 615546), Cappello et al. (2013) identified compound heterozygous mutations in the FAT4 gene: a c.7123G-A transition in exon 7, resulting in a glu2375-to-lys (E2375K) substitution in the CR23 domain, and a c.9481G-T transversion in exon 9, resulting in a glu3161-to-ter (E3161X; 612411.0004) substitution in the CR30 domain. The mutations segregated with the disorder in this family, and E2375K was not present in the dbSNP or 1000 Genomes Project databases. Glu2375 chelates calcium within the cadherin interdomain linker region. The patient had previously been reported as patient 6 by Mansour et al. (2012).

Hennekam Lymphangiectasia-Lymphedema Syndrome 2

In 3 affected members of a consanguineous Dutch family with Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006), originally reported by Hennekam et al. (1989), Alders et al. (2014) identified a homozygous c.7123G-A transition in the FAT4 gene, resulting in an E2375K substitution at a highly conserved residue. The mutation, which was found using a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family and was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 20 control exomes. Functional studies of the variant were not performed. (In the article by Alders et al. (2014), this mutation was cited as E2375K in some places and as E2375R in others; Hennekam (2014) confirmed that E2375K is correct.)

.0004 VAN MALDERGEM SYNDROME 2
FAT4, GLU3161TER
For discussion of the glu316-to-ter (E316X) mutation in the FAT4 gene that was found in compound heterozygous state in a patient with Van Maldergem syndrome-2 (VMLDS2; 615546) by Cappello et al. (2013), see 612411.0003.

.0005 VAN MALDERGEM SYNDROME 2
FAT4, 2-BP DEL, NT14512
In a patient (F3) with Van Maldergem syndrome-2 (VMLDS2; 615546), Cappello et al. (2013) identified a homozygous 2-bp deletion (c.14512_14513del) in exon 17, resulting in a frameshift and premature termination (Ser4838LeufsTer3). The unaffected parents were heterozygous for the mutation. The patient had previously been reported by Neuhann et al. (2012).

.0006 VAN MALDERGEM SYNDROME 2
FAT4, ARG3819TER
In 2 sibs (F4) with Van Maldergem syndrome-2 (VMLDS2; 615546), Cappello et al. (2013) identified a homozygous c.11455C-T transition in exon 9 of the FAT4 gene, resulting in an arg3819-to-ter (R3819X) substitution in the LGLD domain. The unaffected parents were heterozygous for the mutation.

.0007 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2
FAT4, 6-BP DUP, NT7041
In 2 affected members of a consanguineous family with Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006), Alders et al. (2014) identified a homozygous 6-bp duplication (c.7041_7046dup) in the FAT4 gene, resulting in an in-frame duplication of 2 amino acids (2348_2349dupGlyThr). The family had previously been reported by Al-Gazali et al. (2003). The mutation, which segregated with the disorder in the family, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. Functional studies of the variant were not performed.

.0008 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2
FAT4, 1-BP DEL, 1195C
In a female patient with Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006), Alders et al. (2014) identified compound heterozygous mutations in the FAT4 gene: a 1-bp deletion (c.1195delC), resulting in a frameshift and premature termination (Leu399SerfsTer19), and a c.12851C-T transition, resulting in a ser4284-to-phe (S4284F; 612411.0009) substitution at a highly conserved residue. The mutations were not present in the dbSNP or 1000 Genomes Project databases. The c.1195delC mutation was not present in the Exome Sequencing Project database, but the S4284G variant was found in 1 of 1,302 alleles in this database. Functional studies of the variants were not performed.

.0009 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2
FAT4, SER4284PHE
For discussion of the ser428-to-phe (S428F) mutation in the FAT4 gene that was found in compound heterozygous state in a patient with Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006) by Alders et al. (2014), see 612411.0008.

.0010 HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2
FAT4, IVS7AS, A-C, -2
In a patient with Hennekam lymphangiectasia-lymphedema syndrome-2 (HKLLS2; 616006), Alders et al. (2014) identified a homozygous A-to-C transversion (c.7200-2A-C) in the exon 8 splice acceptor site. The mutation was predicted to result in the deletion of 2 amino acids, 2400_2401delSerTyr, but mRNA from the patient was not available to confirm this effect. The mutation, which segregated with the disorder in the family, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases.

Tags: 4q28.1

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