HGNC Approved Gene Symbol: FRMD5
Cytogenetic location: 15q15.3 Genomic coordinates (GRCh38): 15:43,870,764-44,199,473 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q15.3 | Neurodevelopmental disorder with eye movement abnormalities and ataxia | 620094 | Autosomal dominant | 3 |
The FERM domain is composed of 3 subdomains that fold independently and closely associate with one another in a cloverleaf configuration. FRMD5 is a FERM domain-containing protein that localizes to adherens junctions and stabilizes cell-cell contacts (Wang et al., 2012).
Wang et al. (2012) reported that the deduced 570-amino acid FRMD5 protein has a FERM domain in its N-terminal half, followed by a FERM-adjacent (FA) domain and a long C-terminal domain. In transfected HeLa cells, fluorescence-tagged FRMD5 localized to cell-cell contacts with markers of adherens junctions, but not tight junctions.
In Drosophila, Lu et al. (2022) found expression of the orthologous FRMD5 gene, CG5022, in a subset of neurons, but not glial cells, in the central nervous system. In the adult fly brain, CG5022 was observed in the optic lobes, antennal lobes, and mushroom bodies, as well as in other brain regions. The authors noted that FRMD5 is also expressed in the human central nervous system.
By examining a microarray database, Wang et al. (2012) found that FRMD5 expression was downregulated in colorectal and breast cancers. Immunohistochemistry showed that FRMD5 expression was low in renal carcinomas compared with adjacent tissue. Coimmunoprecipitation analysis of H1299 human lung cancer cells revealed that FRMD5 interacted with the adherens junction proteins p120-catenin (CTNND1; 601045) and E-cadherin (CDHE; 192090). Mutation analysis showed that the C-terminal domain of FRMD5 mediated interaction with p120-catenin. In nude mice, knockdown of Frmd5 in H1299 cells promoted cell migration and invasion and increased tumor development.
Hu et al. (2014) found that FRMD5 downregulated cell migration in human lung cancer cells by interacting with integrin beta-5 (ITGB5; 147561) and by inhibiting the kinase activity of ROCK1 (601702). Domain analysis revealed that the FERM domain of FRMD5 interacted with the cytoplasmic tail of ITGB5, whereas the FA domain of FRMD5 interacted with ROCK1.
Wang et al. (2012) stated that the FRMD5 gene maps to chromosome 15q15.3.
In 8 unrelated patients with neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA; 620094), Lu et al. (2022) identified 7 different heterozygous missense mutations in the FRMD5 gene (616309.0001-616309.0005). The mutations, which were found by exome sequencing, were not present in the gnomAD database. The mutations occurred de novo in 6 patients; paternal DNA was not available for the other 2 individuals, but the mother did not carry the mutation in either case. Five of the mutations clustered within a few amino acids (349-354) in the FA domain. Studies of patient cells were not performed, but functional studies of some of the mutations in CG5022-null Drosophila demonstrated that they cause a partial loss-of-function effect with a dominant-negative effect (see ANIMAL MODEL).
Lu et al. (2022) found that loss of the FRMD5 ortholog in Drosophila (CG5022) resulted in heat-induced seizures. Mutant flies were unable to climb properly and showed wing fluttering, leg twitching, and abdominal muscle contractions. These defects could be rescued by expression of the wildtype gene, but not by 3 missense mutations (S351G, 616309.0002; C352R, 616309.0003; and Y546C, 616309.0005) that were identified in humans with NEDEMA. Mutant flies also showed defective responses to light, with electroretinogram (ERG) studies indicating defects in synaptic transmission between presynaptic photoreceptors and postsynaptic lamina cells in an age-dependent manner. This phenotype was fully rescued by wildtype FRMD5, but not by 2 of the human missense mutations (S351G and Y546C). In addition, overexpression of the wildtype gene was toxic to the flies, but overexpression of selected human variants was not as toxic, again illustrating that they result in a partial loss of function. The human mutations acted in a dominant-negative manner.
In an 8-year-old boy (patient 2) with neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA; 620094), Lu et al. (2022) identified a de novo heterozygous c.1051A-G transition (c.1051A-G, NM_032892.5) in the FRMD5 gene, resulting in a ser351-to-gly (S351G) substitution at a highly conserved residue in the FA domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Studies of patient cells were not performed, but rescue experiments in CG5022-null Drosophila showed that the mutation causes a partial loss-of-function effect and acts in a dominant-negative manner. The patient had a severe phenotype with onset of refractory seizures in infancy. He was unable to speak or walk at 8 years of age; nystagmus was present.
In a 27-year-old woman (patient 3) with neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA; 620094), Lu et al. (2022) identified a de novo heterozygous c.1053C-G transversion (c.1053C-G, NM_032892.5) in the FRMD5 gene, resulting in a ser351-to-arg (S351R) substitution at a highly conserved residue in the FA domain. The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Studies of patient cells were not performed, but rescue experiments in CG5022-null Drosophila showed that the mutation causes a partial loss-of-function effect. The patient had borderline intellectual disability, opsoclonus, myoclonus, and dystonia.
In 2 unrelated men (patients 4 and 5) with neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA; 620094), Lu et al. (2022) identified a de novo heterozygous c.1054T-C transition (c.1054T-C, NM_032892.5) in the FRMD5 gene, resulting in a cys352-to-arg (C352R) substitution in the FA domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Studies of patient cells were not performed, but rescue experiments in CG5022-null Drosophila showed that the mutation causes a partial loss-of-function effect and acts in a dominant-negative manner. The patients had hypotonia, abnormal movements, ataxia, and nystagmus; only 1 had evidence of seizures.
In a 9-year-old girl (patient 6) with neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA; 620094), Lu et al. (2022) identified a de novo heterozygous c.1060T-C transition (c.1060T-C, NM_032892.5) in the FRMD5 gene, resulting in a ser354-to-pro (S354P) substitution at a conserved residue in the FA domain. The mutation, which was found by trio-based exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patient had opsoclonus, hypotonia, and ataxia; she did not have seizures.
In a 15.5-year-old boy (patient 8) with neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA; 620094), Lu et al. (2022) identified a heterozygous c.1637A-G transition (c.1637A-G, NM_032892.5) in the FRMD5 gene, resulting in a tyr546-to-cys (Y546C) substitution at a highly conserved residue adjacent to the FA domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. The variant was not found in the mother; the father was not available for study. Studies of patient cells were not performed, but rescue experiments in CG5022-null Drosophila showed that the mutation causes a partial loss-of-function effect. The patient had hypotonia, spasticity, esotropia, and EEG abnormalities.
Hu, J., Niu, M., Li, X., Lu, D., Cui, J., Xu, W., Li, G., Zhan, J., Zhang, H. FERM domain-containing protein FRMD5 regulates cell motility via binding to integrin beta-5 subunit and ROCK1. FEBS Lett. 588: 4348-4356, 2014. [PubMed: 25448675] [Full Text: https://doi.org/10.1016/j.febslet.2014.10.012]
Lu, S., Ma, M., Mao, X., Bacino, C. A., Jankovic, J., Sutton, V. R., Bartley, J. A., Wang, X., Rosenfeld, J. A., Beleza-Meireles, A., Chauhan, J., Pan, X., Li, M., Liu, P., Prescott, K., Amin, S., Davies, G., Wangler, M. F., Dai, Y., Bellen, H. J. De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement. Am. J. Hum. Genet. 109: 1932-1943, 2022. [PubMed: 36206744] [Full Text: https://doi.org/10.1016/j.ajhg.2022.09.005]
Wang, T., Pei, X., Zhan, J., Hu, J., Yu, Y., Zhang, H. FERM-containing protein FRMD5 is a p120-catenin interacting protein that regulates tumor progression. FEBS Lett. 586: 3044-3050, 2012. [PubMed: 22846708] [Full Text: https://doi.org/10.1016/j.febslet.2012.07.019]