Alternative titles; symbols
HGNC Approved Gene Symbol: PLS1
Cytogenetic location: 3q23 Genomic coordinates (GRCh38): 3:142,596,393-142,713,664 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q23 | Deafness, autosomal dominant 76 | 618787 | Autosomal dominant | 3 |
Fimbrin is an actin-bundling protein that was originally discovered in chicken intestinal brush border microvilli. By screening a human small intestine cDNA library with a chicken fimbrin cDNA, Lin et al. (1994) identified a cDNA encoding I-plastin. Northern blot analysis revealed that I-plastin was expressed as a 3.7-kb mRNA in human colon and small intestine. A survey of rat tissues detected I-plastin expression primarily in the intestine, with a lower level in the kidneys. By immunofluorescence, Lin et al. (1994) localized I-plastin to the brush border of the human small intestine and colon. The predicted 629-amino acid protein is 86%, 75%, and 73% identical to chicken fimbrin, human T-plastin (PLS3; 300131), and L-plastin (LCP1; 153430), respectively. I-plastin migrated as a 68-kD protein on Western blots of human small intestine and colon extracts. Lin et al. (1994) concluded that I-plastin is the human homolog of chicken intestine fimbrin.
Lin et al. (1994) mapped the PLS1 gene to chromosome 3 by PCR of somatic cell hybrids.
Stumpf (2020) mapped the PLS1 gene to chromosome 3q23 based on an alignment of the PLS1 sequence (GenBank BC031083) with the genomic sequence (GRCh38).
Lin et al. (1994) found that recombinant I-plastin crosslinked actin filaments into bundles in the absence of calcium but not in its presence.
In affected members of a 3-generation Roma family segregating autosomal dominant congenital hearing loss (DFNA76; 618787), Schrauwen et al. (2019) identified heterozygosity for a missense mutation in the PLS1 gene (L363F; 602734.0001).
In affected members of 3 unrelated families with autosomal dominant nonsyndromic hearing loss, Morgan et al. (2019) identified heterozygosity for missense mutations in the PLS1 gene (602734.0002-602734.0004) that were not found in public variant databases. Sanger sequencing confirmed segregation with disease in all 3 families.
In affected members of a Turkish family with DFNA76, Diaz-Horta et al. (2019) identified heterozygosity for the same missense mutation in the PLS1 gene (E269K; 602734.0002) that had been identified by Morgan et al. (2019).
Grimm-Gunter et al. (2009) created Pls1-knockout mice on a C57BL/6 background. The Pls1-null mice were fertile and displayed a normal reproductive rate. Sex distribution of pups and life span were not significantly altered. Microscopic examination of HE-stained intestinal epithelium showed no obvious changes in the organization of villi or crypts. However, transmission electron microscopic analysis of intestinal sections showed that the microvilli were shorter, constricted at their base, and lacked rootlets. The morphologic changes resulted in increased fragility of the epithelium, demonstrated by increased sensitivity of the brush border to biochemical manipulations, decreased transepithelial resistance, and increased sensitivity to dextran sodium sulfate-induced colitis.
Taylor et al. (2015) determined that Pls1-null mice have a moderate and progressive form of hearing loss across all frequencies. The auditory hair cells of the knockout mice developed normally, but the stereocilia of inner hair cells were reduced in width and length. The outer hair cell stereocilia were comparatively less affected, but showed signs of degeneration in aging mice. Taylor et al. (2015) noted that C57BL/6 mice are known for increased susceptibility to age-related hearing loss; however, the Pls1-null mice exhibited a more significant hearing loss phenotype starting at an earlier age.
In a sister and brother and their mother from a 3-generation Roma family (family 6012) with autosomal dominant congenital deafness (DFNA76; 618787), Schrauwen et al. (2019) identified heterozygosity for a c.1087C-T transition (c.1087C-T, NM_002670.2) in the PLS1 gene, resulting in a leu363-to-phe (L363F) substitution at a highly conserved residue within the calponin-homology-2 (CH2) domain. The mutation status of the affected maternal grandmother was not reported.
In a girl, her mother, and her maternal uncle from an Italian family (family 1) with nonsyndromic sensorineural hearing loss (DFNA76; 618787), Morgan et al. (2019) identified heterozygosity for a c.805G-A transition (c.805G-A, NM_002670.2) in the PLS1 gene, resulting in a glu269-to-lys (E269K) substitution at a highly conserved residue within the first actin-binding domain. The mutation was not found in 3 unaffected relatives or in an internal database of 1,000 genomes or in public variant databases.
In affected members of a Turkish family with DFNA76, Diaz-Horta et al. (2019) identified heterozygosity for the E269K mutation in the PLS1 gene. Molecular modeling suggested that the mutation would affect the ability of PLS1 to direct the formation of ACTB (102630) bundles found in microvilli and stereocilia.
In a boy, his affected father and paternal grandfather and an affected second cousin from a large 4-generation Irish-German American family (family 2) with nonsyndromic sensorineural hearing loss (DFNA76; 618787), Morgan et al. (2019) identified heterozygosity for a c.713T-G transversion (c.713T-G, NM_002670.2) in the PLS1 gene, resulting in a leu238-to-arg (L238R) substitution at a highly conserved residue within the first actin-binding domain. The mutation was not found in the proband's unaffected brother, mother, or paternal grandmother, or in the gnomAD database.
In a girl, her father, and her paternal grandfather from a 3-generation French family (family 3) with nonsyndromic sensorineural hearing loss (DFNA76; 618787), Morgan et al. (2019) identified heterozygosity for a c.383T-C transition (c.383T-C, NM_002670.2) in the PLS1 gene, resulting in a phe128-to-ser (F128S) substitution at a highly conserved residue within the first actin-binding domain. The mutation was not found in the proband's unaffected mother.
Diaz-Horta, O., Bademci, G., Tokgoz-Yilmaz, S., Guo, S., Zafeer, F., Sineni, C. J., Duman, D., Farooq, A., Tekin, M. Novel variant pE269K confirms causative role of PLA1 mutations in autosomal dominant hearing loss. Clin. Genet. 96: 575-578, 2019. [PubMed: 31432506] [Full Text: https://doi.org/10.1111/cge.13626]
Grimm-Gunter, E-M. S., Revenu, C., Ramos, S., Hurbain, I., Smyth, N., Ferrary, E., Louvard, D., Robine, S., Rivero, F. Plastin 1 binds to keratin and is required for terminal web assembly in the intestinal epithelium. Molec. Biol. Cell 20: 2549-2562, 2009. [PubMed: 19321664] [Full Text: https://doi.org/10.1091/mbc.e08-10-1030]
Lin, C.-S., Shen, W., Chen, Z. P., Tu, Y.-H., Matsudaira, P. Identification of I-plastin, a human fimbrin isoform expressed in intestine and kidney. Molec. Cell. Biol. 14: 2457-2467, 1994. [PubMed: 8139549] [Full Text: https://doi.org/10.1128/mcb.14.4.2457-2467.1994]
Morgan, A., Koboldt, D. C., Barrie, E. S., Crist, E. R., Garcia, G. G., Mezzavilla, M., Faletra, F., Mosher, T. M., Wilson, R. K., Blanchet, C., Manickam, K., Roux, A.-F., Gasparini, P., Dell'Orco, D., Girotto, G. Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss. Hum. Mutat. 40: 2286-2295, 2019. [PubMed: 31397523] [Full Text: https://doi.org/10.1002/humu.23891]
Schrauwen, I., Melegh, B. I., Chakchouk, I., Acharya, A. Nasir, A., Poston, A., Cornejo-Sanchez, D. M., Szabo, Z., Karosi, T. Bene, J., Melegh, B., Leal, S. M. Hearing impairment locus heterogeneity and identification of PLS1 as a new autosomal dominant gene in Hungarian Roma. Europ. J. Hum. Genet. 27: 869-878, 2019. [PubMed: 30872814] [Full Text: https://doi.org/10.1038/s41431-019-0372-y]
Stumpf, A. M. Personal Communication. Baltimore, Md. 02/21/2020.
Taylor, R., Bullen, A., Johnson, S. L., Grimm-Gunter, E.-M., Rivero, F., Marcotti, W., Forge, A., Daudet, N. Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice. Hum. Molec. Genet. 24: 37-49, 2015. [PubMed: 25124451] [Full Text: https://doi.org/10.1093/hmg/ddu417]