Alternative titles; symbols
HGNC Approved Gene Symbol: ESPN
Cytogenetic location: 1p36.31 Genomic coordinates (GRCh38) : 1:6,424,776-6,461,370 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.31 | ?Usher syndrome, type 1M | 618632 | Autosomal recessive | 3 |
| Deafness, autosomal recessive 36 | 609006 | Autosomal recessive | 3 | |
| Deafness, neurosensory, without vestibular involvement, autosomal dominant | 609006 | Autosomal recessive | 3 |
ESPN is a myosin III (see MYO3A, 606808) cargo protein that is essential for hearing (Ebrahim et al., 2016).
Ectoplasmic specializations are membrane-cytoskeletal assemblages found in Sertoli cells at sites of attachment to elongate spermatids or neighboring Sertoli cells. Bartles et al. (1996) identified the rat actin-bundling protein espin, which is localized to ectoplasmic specializations. The 836-amino acid espin protein had a molecular mass of approximately 110 kD in SDS gels. Northern blot analysis detected a 2.9-kb espin transcript only in rat testis; a minor 1.7-kb transcript was detected in small intestine and kidney.
Bartles et al. (1998) identified a 30-kD, 253-amino acid isoform of rat espin that localized to brush border microvilli in the intestine and kidney. Espin and small espin share a 167-amino acid C-terminal peptide that includes a 116-amino acid C-terminal actin-bundling module that is necessary and sufficient for actin bundle formation in vitro; however, they contain different N termini. Bartles et al. (1998) and Chen et al. (1999) determined that unlike many actin-bundling proteins, the rat espins bind actin filaments with high affinity, and their actin-bundling activities are not inhibited by calcium.
Naz et al. (2004) cloned human ESPN. The deduced 854-amino acid protein has 8 ankyrin-like repeats at the N terminus, 2 proline-rich regions, a consensus site for ATP or GTP binding (P loop), which is contained within an actin-binding WH2 motif, and a coiled coil domain. The human protein shares 83% and 86% sequence identity with the mouse and rat homologs, respectively. PCR analysis of human fetal inner ear cDNA revealed expression of ESPN in the inner ear. ESPN expression constructs lacking either one or both of the actin-binding sites were unable to crosslink actin filaments when transfected into BHK fibroblasts.
Using immunolocalization, Ebrahim et al. (2016) showed that Espn1, an isoform of mouse Espn, localized to the tips of stereocilia in mouse hair bundles.
Chen et al. (1999) confirmed that mouse espin and small espin are splice variants of a single gene. The mouse espin gene contains 11 exons and spans more than 15 kb.
Naz et al. (2004) determined that the human ESPN gene contains 13 exons.
Gross (2022) mapped the ESPN gene to chromosome 1p36.31 based on an alignment of the ESPN sequence (GenBank AY203958) with the genomic sequence (GRCh38).
Zheng et al. (2000) mapped the mouse espin gene to the same region of chromosome 4 as the 'jerker' mouse mutation.
Using ectopic expression in COS-7 cells, Ebrahim et al. (2016) showed that Espn1 and Espnl (619974) interacted and cooperated with Myo3a and Myo3b (610040) to differentially control filopodia growth.
Deafness, Autosomal Recessive 36, with or without Deafness
In 2 consanguineous Pakistani families segregating recessively inherited deafness and vestibular areflexia (DFNB36; 609006), Naz et al. (2004) identified 2 different homozygous frameshift mutations in the ESPN gene (606351.0001-606351.0002).
Boulouiz et al. (2008) identified a homozygous mutation in the ESPN gene (606351.0007) in 6 affected members of a consanguineous Moroccan family with autosomal recessive deafness without vestibular involvement (609006). If translated, the mutant protein would lack the WH2 domain, which is important for binding actin monomers. The results were consistent with a loss-of-function effect.
Deafness, Autosomal Dominant, without Vestibular Involvement
Donaudy et al. (2006) reported 4 ESPN mutations in patients affected by autosomal dominant hearing loss without vestibular involvement (see 609006): S719R (606351.0003), D744N (606351.0004), R774Q (606351.0005), and K848del (606351.0006). To determine whether the mutated ESPN alleles affected the biologic activity of the corresponding espin proteins in vivo, their ability to target and elongate the parallel actin bundles of brush border microvilli was investigated in transfected epithelial cells. For 3 mutated alleles, clear abnormalities in microvillar length or distribution were obtained. Thus, the ESPN gene is associated with either autosomal recessive or autosomal dominant inheritance of deafness. This is true also of the connexin-26 gene (CX26; 121011). Indeed, mutations in one of the most prevalent deafness alleles in the CX26 gene can be inherited in either a dominant or recessive mode (Rabionet et al., 2000).
Usher Syndrome, Type 1M
In affected members of a large Pakistani family with prelingual sensorineural hearing loss, vestibular dysfunction, and retinitis pigmentosa (USH1M; 618632), Ahmed et al. (2018) identified homozygosity for an in-frame 18-bp deletion (606351.0008) that segregated with disease.
Zheng et al. (2000) determined that espins are present in hair cell stereocilia and uncovered a connection between the espin gene and jerker mouse, a recessive mutation that causes hair cell degeneration, deafness, and vestibular dysfunction. The tissues of jerker mice did not accumulate espin proteins but contained normal levels of espin mRNAs. The authors identified a frameshift mutation in the espin gene of jerker mice that affected the espin C-terminal actin-bundling module. These data suggested that jerker mice are espin null and that the jerker phenotype results from a mutation in the espin gene.
Ebrahim et al. (2016) found that mice lacking Espn1 but expressing the short Espn isoforms had normal hearing. However, loss of Espn1 dramatically altered the slope of the stereocilia staircase in a subset of hair cells. In addition, Myo3b was no longer present at stereocilia tips of extrastriolar hair cells of Espn1 -/- mice
In a consanguineous Pakistani family segregating autosomal recessive neurosensory deafness and vestibular areflexia (DFNB36; 609006), Naz et al. (2004) identified a homozygous 4-bp deletion (2469delGTCA) in exon 13 of the ESPN gene, leading to a stop codon at nucleotide 2533. The resultant protein is predicted to lack one of the C-terminal actin-binding sites necessary for espin activity.
In a consanguineous Pakistani family (PKSR5A) segregating autosomal recessive neurosensory deafness and vestibular areflexia (DFNB36; 609006), Naz et al. (2004) identified a homozygous 4-bp deletion (1988delAGAG) in exon 9 of the ESPN gene, causing truncation at nucleotide 1990. The resultant protein is predicted to lack the actin-bundling module necessary for espin activity.
Ahmed et al. (2018) analyzed the function of the 1988delAGAG mutant (Lys663ThrfsTer1) in transfected heterologous epithelial cells and observed that, unlike wildtype ESPN, the mutant failed to target or elongate microvilli. Similarly, in mouse inner ear sensory epithelia, the mutant failed to target to stereocilia, and the protein appeared distributed throughout the cochlear hair cell bodies.
In a small Italian kindred in which 2 affected individuals in 2 generations showed autosomal dominant progressive sensorineural hearing impairment (see 609006), Donaudy et al. (2006) detected an A-to-C transversion at nucleotide position 2155 in the ESPN gene that led to a substitution of arg for ser at codon 719 (S719R). Hearing loss started in the second decade and led to mild to moderate hearing loss in the fourth decade. Mainly high frequencies were involved. There was no vestibular involvement.
In an Italian patient with severe bilateral sensorineural hearing loss involving all frequencies (see 609006), Donaudy et al. (2006) found heterozygosity for a G-to-A transition at nucleotide 2230 of the ESPN gene that caused an asp744-to-asn amino acid substitution (D744N). There was no vestibular involvement.
In an Italian patient with late-onset mild bilateral sensorineural hearing loss (see 609006), Donaudy et al. (2006) found a sporadic G-to-A transition at nucleotide 2321 of the ESPN gene that resulted in substitution of gln for arg at codon 774 (R774Q). Hearing loss was mainly high frequency, but some involvement was found at all frequencies.
In a 4-year-old Spanish patient with severe bilateral sensorineural hearing impairment without vestibular involvement (see 609006), Donaudy et al. (2006) detected a sporadic 3-nucleotide deletion in the ESPN gene (2541-2543delAAG) leading to loss of lys848 in the C-terminal peptide (delK848). The lys848 residue of the ESPN protein is highly conserved across species.
In 6 affected members of a consanguineous Moroccan family with autosomal recessive deafness without vestibular involvement (609006), Boulouiz et al. (2008) identified a homozygous 1-bp insertion (1757insG) in the ESPN gene, predicted to result in a frameshift and premature protein truncation. If translated, the mutant protein would lack the WH2 domain, which is important for binding actin monomers. The results were consistent with a loss-of-function effect.
In affected members of a large Pakistani family (PKDF1051) with prelingual sensorineural hearing loss, vestibular dysfunction, and retinitis pigmentosa (USH1M; 618632), Ahmed et al. (2018) identified homozygosity for an in-frame 18-bp deletion (c.2369_2386delAGGCGGGACCTCCTGCGG) within exon 11 of the ESPN gene, predicted to remove 6 evolutionarily conserved residues (790-795delRRDLLR). The mutation segregated fully with disease in the family and was not found in 224 ethnically matched chromosomes from the ExAC database or in the NHLBI-ESP database. Functional analysis in transfected heterologous epithelial cells showed that the mutant protein retains microvillar targeting ability but lacks the microvillar elongation activity of wildtype ESPN. Similarly, in mouse inner ear sensory epithelia, the mutant localized along the length of the stereocilia of cochlear hair cells but failed to overelongate them. F-actin cosedimentation assays revealed that the mutant retained residual binding to F-actin (approximately 15% of that of wildtype ESPN), but had impaired bundling function compared to wildtype.
Ahmed, Z. M., Jaworek, T., Sarangdhar, G. N., Zheng, L., Gul, K., Khan, S. N., Friedman, T. B., Sisk, R. A., Bartles, J. R., Riazuddin, S., Riazuddin, S. Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment. J. Med. Genet. 55: 479-488, 2018. [PubMed: 29572253] [Full Text: https://doi.org/10.1136/jmedgenet-2017-105221]
Bartles, J. R., Wierda, A., Zheng, L. Identification and characterization of espin, an actin-binding protein localized to the F-actin-rich junctional plaques of Sertoli cell ectoplasmic specializations. J. Cell Sci. 109: 1229-1239, 1996. [PubMed: 8799813] [Full Text: https://doi.org/10.1242/jcs.109.6.1229]
Bartles, J. R., Zheng, L., Li, A., Wierda, A., Chen, B. Small espin: a third actin-bundling protein and potential forked protein ortholog in brush border microvilli. J. Cell Biol. 143: 107-119, 1998. [PubMed: 9763424] [Full Text: https://doi.org/10.1083/jcb.143.1.107]
Boulouiz, R., Li, Y., Soualhine, H., Abidi, O., Chafik, A., Nurnberg, G., Becker, C., Nurnberg, P., Kubisch, C., Wollnik, B., Barakat, A. A novel mutation in the Espin gene causes autosomal recessive nonsyndromic hearing loss but no apparent vestibular dysfunction in a Moroccan family. (Letter) Am. J. Med. Genet. 146A: 3086-3089, 2008. [PubMed: 18973245] [Full Text: https://doi.org/10.1002/ajmg.a.32525]
Chen, B., Li, A., Wang, D., Wang, M., Zheng, L., Bartles, J. R. Espin contains an additional actin-binding site in its N terminus and is a major actin-bundling protein of the Sertoli cell-spermatid ectoplasmic specialization junctional plaque. Molec. Biol. Cell 10: 4327-4339, 1999. [PubMed: 10588661] [Full Text: https://doi.org/10.1091/mbc.10.12.4327]
Donaudy, F., Zheng, L., Ficarella, R., Ballana, E., Carella, M., Melchionda, S., Estivill, X., Bartles, J. R., Gasparini, P. Espin gene (ESPN) mutations associated with autosomal dominant hearing loss cause defects in microvillar elongation or organisation. (Letter) J. Med. Genet. 43: 157-161, 2006. [PubMed: 15930085] [Full Text: https://doi.org/10.1136/jmg.2005.032086]
Ebrahim, S., Avenarius, M. R., Grati, M., Krey, J. F., Windsor, A. M., Sousa, A. D., Ballesteros, A., Cui, R., Millis, B. A., Salles, F. T., Baird, M. A., Davidson, M. W., Jones, S. M., Choi, D., Dong, L., Raval, M. H., Yengo, C. M., Barr-Gillespie, P. G., Kachar, B. Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like. Nature Commun. 7: 10833, 2016. Note: Erratum: Nature Commun. 8: 161133, 2017. [PubMed: 26926603] [Full Text: https://doi.org/10.1038/ncomms10833]
Gross, M. B. Personal Communication. Baltimore, Md. 7/25/2022.
Naz, S., Griffith, A. J., Riazuddin, S., Hampton, L. L., Battey, J. F., Jr., Khan, S. N., Riazuddin, S., Wilcox, E. R., Friedman, T. B. Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J. Med. Genet. 41: 591-595, 2004. [PubMed: 15286153] [Full Text: https://doi.org/10.1136/jmg.2004.018523]
Rabionet, R., Gasparini, P., Estivill, X. Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins. Hum. Mutat. 16: 190-202, 2000. [PubMed: 10980526] [Full Text: https://doi.org/10.1002/1098-1004(200009)16:3<190::AID-HUMU2>3.0.CO;2-I]
Zheng, L., Sekerkova, G., Vranich, K., Tilney, L. G., Mugnaini, E., Bartles, J. R. The deaf jerker mouse has a mutation in the gene encoding the espin actin-bundling proteins of hair cell stereocilia and lacks espins. Cell 102: 377-385, 2000. [PubMed: 10975527] [Full Text: https://doi.org/10.1016/s0092-8674(00)00042-8]