Alternative titles; symbols
HGNC Approved Gene Symbol: FERMT1
SNOMEDCT: 238836000;
Cytogenetic location: 20p12.3 Genomic coordinates (GRCh38) : 20:6,074,845-6,123,030 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.3 | Kindler syndrome | 173650 | Autosomal recessive | 3 |
Using microarray analysis of genes showing altered expression in several tumor tissues, followed by PCR of pooled colon tumor cDNA, Weinstein et al. (2003) cloned a full-length URP1 cDNA, encoding a protein with significant homology to the C. elegans Unc112 protein. The deduced 677-amino acid URP1 protein has a calculated molecular mass of 77.4 kD. In its C-terminal half, URP1 contains 2 FERM domains flanking a pleckstrin homology (PH) domain. URP1 shares 65.5% identity with MIG2 (607746) and 58.7% identity with URP2 (607901). All 3 proteins share weak but significant homology with talin-1 (186745) and talin-2 (607349). Northern blot analysis detected strong expression of a 4.4-kb URP1 transcript in brain and skeletal muscle, weaker expression in kidney and placenta, and little to no expression in other tissues.
Using RT-PCR, Jobard et al. (2003) determined that the protein, which they called kindlerin, is expressed in multiple tissues, notably colon, lung, placenta, adrenal, prostate, and cultured keratinocytes.
By Northern blot analysis, Siegel et al. (2003) detected a major 4.9-kb transcript, which they called kindlin-1 (KIND1), at highest levels in keratinocyte, colon, kidney, and placenta and at lower levels in heart, skeletal muscle, liver, and small intestine. An additional, approximately 5.8-kb transcript was detected in colon. Using a polyclonal antibody raised against a C-terminal synthetic KIND1 peptide, they localized the protein solely within the epidermis and particularly in basal keratinocytes.
Weinstein et al. (2003) determined that the URP1 gene contains 15 exons, spans about 50 kb, and is oriented in the centromere-to-telomere direction. The initiator methionine is in exon 2.
Weinstein et al. (2003) determined that expression of URP1 was significantly upregulated in 70% of colon carcinomas and in 60% of lung carcinomas tested. In 3 of 6 lung tumors, the average increase in URP1 expression was 60-fold.
Siegel et al. (2003) demonstrated that KIND1 colocalizes with vinculin and is therefore a component of focal contacts, which are structures involved in membrane-substratum attachment in cultured cells. They also found that KIND1 can associate to some extent with filamentous actin.
Kloeker et al. (2004) found the kindlerin expression was responsive to TGF-beta (TGFB; 190180). Upon TGFB stimulation, a portion of kindlerin relocalized from focal adhesions to membrane ruffles, particularly to sites of cell-cell contact. In pull-down assays, kindlerin formed complexes with integrin-beta cytoplasmic domains in a dose-dependent manner. Kindlerin overexpression did not alter integrin activation, but reduction of kindlerin protein levels by small interfering RNA perturbed cell spreading.
Jobard et al. (2003) identified mutations in the FERMT1 gene (607900.0001-607900.0004) in 4 consanguineous kindreds with Kindler syndrome (KNDLRS; 173650), an autosomal recessive dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling. Three of the 4 mutations were predicted to result in truncation of the protein, with loss of the FERM and PH domains. Jobard et al. (2003) proposed that kindlerin may normally play a role in cell adhesion processes via integrin signaling.
Siegel et al. (2003) identified loss-of-function mutations in the FERMT1 gene (607900.0005-607900.0006) in patients with Kindler syndrome. Because kindlin-1 is a human homolog of the C. elegans protein Unc112, a membrane-associated structural/signaling protein that had been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM), Siegel et al. (2003) suggested that Kindler syndrome is the first skin fragility disorder shown to be caused by a defect in actin-ECM linkage rather than keratin-ECM linkage.
Heinemann et al. (2011) demonstrated that kindlin-1-deficient keratinocytes respond to cell stress by upregulating the expression of several cytokines, including IL20 (605619), IL24 (604136), TGFB2 (190220), IL1F5 (605507), PDGFB (190040), and CTGF (121009). These upregulated cytokines launch, via paracrine communication, an inflammatory response in the dermis, accompanied by the presence of TGFB, IL6 (147620), and CTGF, with activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins. Heinemann et al. (2011) concluded that their data were consistent with a model in which repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie the mucocutaneous fibrosis in Kindler syndrome.
By genomic sequence analysis, Weinstein et al. (2003) mapped the URP1 gene to chromosome 20p13.
In a consanguineous North African family with Kindler syndrome (KNDLRS; 173650), Jobard et al. (2003) determined that all 3 affected individuals were homozygous for a T-C transition in the donor splice site of intron 3 of the FERMT1 gene. The mutation is predicted to result in loss of exon 3 from the transcript.
In a consanguineous North African family with Kindler syndrome (KNDLRS; 173650), Jobard et al. (2003) determined that the 3 affected individuals were homozygous for a 787C-T transition in exon 6 of the FERMT1 gene. The mutation is predicted to result in a premature stop codon at glutamine 263, leading to loss of the FERM and PH domains of the protein.
In a consanguineous North African family with Kindler syndrome (KNDLRS; 173650), Jobard et al. (2003) determined that both affected individuals were homozygous for a 1-bp insertion (1714insA) in exon 13 of the FERMT1 gene. The mutation was predicted to result in a premature stop codon and loss of the PH domain of the protein.
In a consanguineous North African family with Kindler syndrome (KNDLRS; 173650), Jobard et al. (2003) determined that both affected individuals were homozygous for a 1-bp deletion (464delA) in exon 4 of the FERMT1 gene. The mutation was predicted to result in loss of the FERM and PH domains of the protein.
In 26 patients from Bocas del Toro, Panama, with Kindler syndrome (KNDLRS; 173650), Siegel et al. (2003) identified homozygosity for an 811C-T transition in exon 6 of the FERMT1 gene, resulting in an arg271-to-ter (R271X) mutation. They identified the same mutation in patients from 2 white American families and 1 Middle Eastern Omani family. Haplotype analysis indicated that the mutation probably arose on different genetic backgrounds in these geographically diverse families.
In a British and a Turkish patient with Kindler syndrome (KNDLRS; 173650), Siegel et al. (2003) identified homozygosity for an 862C-T transition in exon 7 of the FERMT1 gene, resulting in an arg288-to-ter (R288X; 607900.0002) mutation. Haplotype analysis indicated that the mutation occurred on different genetic backgrounds.
Heinemann, A., He, Y., Zimina, E., Boerries, M., Busch, H., Chmel, N., Kurz, T., Bruckner-Tuderman, L., Has, C. Induction of phenotype modifying cytokines by FERMT1 mutations. Hum. Mutat. 32: 397-406, 2011. [PubMed: 21309038] [Full Text: https://doi.org/10.1002/humu.21449]
Jobard, F., Bouadjar, B., Caux, F., Hadj-Rabia, S., Has, C., Matsuda, F., Weissenbach, J., Lathrop, M., Prud'homme, J.-F., Fischer, J. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum. Molec. Genet. 12: 925-935, 2003. [PubMed: 12668616] [Full Text: https://doi.org/10.1093/hmg/ddg097]
Kloeker, S., Major, M. B., Calderwood, D. A., Ginsberg, M. H., Jones, D. A., Beckerle, M. C. The Kindler syndrome protein is regulated by transforming growth factor-beta and involved in integrin-mediated adhesion. J. Biol. Chem. 279: 6824-6833, 2004. [PubMed: 14634021] [Full Text: https://doi.org/10.1074/jbc.M307978200]
Siegel, D. H., Ashton, G. H. S., Penagos, H. G., Lee, J. V., Feiler, H. S., Wilhelmsen, K. C., South, A. P., Smith, F. J. D., Prescott, A. R., Wessagowit, V., Oyama, N., Akiyama, M., and 30 others. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am. J. Hum. Genet. 73: 174-187, 2003. [PubMed: 12789646] [Full Text: https://doi.org/10.1086/376609]
Weinstein, E. J., Bourner, M., Head, R., Zakeri, H., Bauer, C., Mazzarella, R. URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas. Biochim. Biophys. Acta 1637: 207-216, 2003. [PubMed: 12697302] [Full Text: https://doi.org/10.1016/s0925-4439(03)00035-8]