Alt. symbols: CDHF14 | FAT-J | CDHR11

Approved name: FAT atypical cadherin 4
Alt. names: FAT tumor suppressor homolog 4 (Drosophila) | cadherin-related family member 11

Location: 4q28.1: 125314918 - 125492932 (+)
Gene type: protein_coding, 5 transcripts.

Scores: LoFtool: 0.323000 | pLI: 1.00000000 | LOEUF: 0.184

HGNC: 23109

NCBI: 79633, RefSeq: NG_033865.1

Ensembl: ENSG00000196159.14

LRG_ | Status: none

OMIM: 612411

Expression | ProteinAtlas

Cadherins are calcium-dependent cell adhesion proteins. FAT4 encodes a protocadherin that complexes with another protocadherin DCHS1 to form an apically located adhesive complex in the developing brain. It is thought to play a key role in the maintenance of planar cell polarity, as well as in inhibition of YAP1-mediated neuroprogenitor cell proliferation and differentiation during cortical brain development (PMID: 24056717). Additionally, based on their associated mammalian loss-of-function phenotypes, this pair is thought to play important roles in lymphatic, skeletal and renal development (PMID: 27381226, 30853441, 31358536, 32182215, 27381226, 28878612).

Biallelic mutations in FAT4 are associated with Hennekam lymphangiectasia-lymphedema syndrome type 2 (HKLLS2) [MIM:616006], an autosomal recessive disorder characterized by generalized lymphatic dysplasia and lymphedema affecting organs such as the intestinal tract, pericardium, lungs, kidneys and limbs. Additional features include cognitive impairment, camptodactyly, hearing loss (in some patients), and characteristic craniofacial features such as a flat face, small ears with thickened helices, hypertelorism, epicanthus, blepharophimosis, flat nasal bridge, small mouth and irregular dentition. This is allelic to another autosomal recessive disorder called Van Maldergem syndrome 2 (VMLDS2) [MIM:615546], which shares some overlapping features. VMLDS2 is characterized by hypotonia, feeding problems, tracheal anomalies, intellectual disability, distinctive facies, auditory malformations resulting in conductive and/or sensorineural hearing loss, osteopenia and skeletal and limb malformations. Some patients have renal hypoplasia or other genitourinary findings. Brain MRI typically shows periventricular nodular heterotopia; subcortical band heterotopia and thinning of the corpus callosum have also been described. Characteristic craniofacial features include flat midface, bitemporal narrowing, hypertelorism, short palpebral fissures, ptosis, epicanthal folds, broad nasal bridge with thickening of the nasal alae, tented upper lip with downturned corners of mouth, high-arched palate, micrognathia, and maxillary hypoplasia. Irregular dentition and thickened gums have also been noted. Recently, the feature of lymphangiectasia as a distinguishing trait of HKLLS2 (in contrast to VMLDS2) has been challenged by the observation of intestinal lymphangiectasia causing significant protein-losing enteropathy in a pediatric patient whose clinical and molecular findings were otherwise consistent with a diagnosis of VMLDS2 (PMID: 31063239). Missense mutations have thus far been the most commonly described disease-associated changes, though nonsense, frameshift, small in-frame deletion/duplications, and splice site mutations have also been reported for either or both conditions. As noted by Alders et al. (2014) and Ivanovski et al. (2018), mutations associated with HKLLS2 appear to be preferentially distributed through the more N-terminal portion of extracellular cadherin repeats, while mutations associated with VMLDS2 have been noted to cluster more C-terminally – either within the cadherin repeats, more distally in the EGF-like and laminin G-like domains, or past the MPDZ-interacting region (PMID:24913602, 29681106). [Load More]