Alternative titles; symbols
HGNC Approved Gene Symbol: SYNE4
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:36,003,307-36,008,813 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.12 | Deafness, autosomal recessive 76 | 615540 | Autosomal recessive | 3 |
SYNE4 localizes to the outer nuclear membrane. SYNE4 is part of a LINC (linker of the cytoskeleton and nucleoskeleton) tethering complex and has a role in cellular positioning of organelles, including the nucleus (Roux et al., 2009).
By searching databases for sequences similar to the Klarsicht/Anc1/SYNE (see SYNE1, 608441) homology (KASH) domain of human NESP2 (SYNE2; 608442), Roux et al. (2009) identified mouse and human SYNE4, which they called NESP4. The deduced 388-amino acid mouse protein has a calculated molecular mass of 42 kD. It has a short leucine zipper near the N terminus, followed by a partial spectrin (see 182860) repeat and a KASH domain that includes a transmembrane segment and a short luminal C-terminal tail. Immunohistochemical analysis revealed expression of Nesp4 in several secretory tissues, including salivary gland, exocrine pancreas, bulbourethral gland, and mammary tissue. Nesp4 was also expressed following differentiation in HC11 mouse mammary cells, which secrete milk proteins. Epitope-tagged Nesp4 localized to the nuclear envelope in transfected human salivary gland cells, and differential permeabilization revealed that the N terminus of Nesp4 was exposed on the outer nuclear membrane.
Horn et al. (2013) identified NESP4 within a region of chromosome 19 linked to progressive high frequency hearing loss. The deduced 404-amino acid NESP4 protein has a leucine zipper near the N terminus, followed by a spectrin repeat, a kinesin (see KLC1, 600025)-binding region, and a C-terminal KASH domain. Immunofluorescence microscopy of mouse cochlear sensory epithelium detected Nesp4 expression in the 3 rows of outer hair cells and 1 row of inner hair cells, but not in other cells, of the cochlea. Within hair cells, Nesp4 localized predominantly to the nuclear envelope.
Roux et al. (2009) stated that LINC complexes are made up of nesprins on the outer nuclear membrane and SUN1 (607723) or SUN2 (613569) on the inner nuclear membrane. The KASH domains of nesprins tether them to the outer nuclear membrane by interacting with SUN proteins across the perinuclear space. Using mutation analysis, Roux et al. (2009) found that the KASH domain of mouse Nesp4 was necessary and sufficient for localization of Nesp4 to the outer nuclear membrane. In HeLa cells, depletion of SUN1 and SUN2 via RNA interference dislodged transfected mouse Nesp4 from the nuclear envelope and caused its redistribution. Coimmunoprecipitation and yeast 2-hybrid analyses revealed that mouse Nesp4 interacted with KIF5B (602809) and several kinesin light chain subunits of microtubule plus-end motor proteins, including KLC1. When overexpressed in human cell lines, Nesp4 behaved as a kinesin cargo protein and caused active polarization of nuclear membrane components, separation of the nucleus from the centrosome, and separation of the Golgi apparatus from the nucleus. Roux et al. (2009) concluded that NESP4 is a kinesin-binding protein that contributes to microtubule-dependent nuclear positioning.
By genomic sequence analysis, Horn et al. (2013) mapped the SYNE4 gene to chromosome 19q13.12.
In 6 patients from 2 unrelated consanguineous Iraqi Jewish families with autosomal recessive deafness-76 (DFNB76; 615540), Horn et al. (2013) identified a homozygous truncating mutation in the SYNE4 gene (c.228_229delAT; 615535.0001). The mutation was found by homozygosity mapping followed by Sanger sequencing of genes within the interval. Mutation carriers had onset of progressive high frequency hearing impairment between birth and 6 years of age. The hearing loss was severe at high frequencies by adulthood. In vitro functional expression studies showed that the mutant proteins resulting from the deletion had abnormal intracellular localization within the cytoplasm. The SYNE4 gene is normally expressed in mechanosensory hair cells where it localizes to the nuclear envelope. Horn et al. (2013) suggested that the mutation compromised the motility of outer hair cells.
Horn et al. (2013) found that Nesp4 -/- mice were born at the expected mendelian ratio, appeared normal, and showed no behavioral abnormalities. Histochemical analysis revealed no abnormalities in secretory epithelial tissues, including salivary and mammary glands and exocrine pancreas. Nursing pups of Nesp4 -/- dams gained weight at a normal rate, indicating absence of mammary dysfunction. Auditory brainstem responses revealed that Nesp4 -/- mice, but not Nesp +/- mice, developed hearing loss that progressed to all frequencies by postnatal day 60. At postnatal day 0, Nesp4 -/- cochlea appeared normal; however, with onset of detectable hearing, Nesp4 -/- outer hair cells showed progressive degeneration, from the base to the apex, with concomitant redistribution of nuclei from the base of outer hair cells to a more apical position. Disruption of the inner hair cells was delayed to postnatal day 180. Sun1 -/- animals showed a similar overall phenotype, with hearing loss and degeneration of cochlear outer hair cells. Sun1 -/- mice also showed loss of Nesp4 from the nuclear envelope of cochlear outer hair cells. Horn et al. (2013) concluded that the LINC proteins NESP4 and SUN1 are necessary for viability and normal morphology of cochlear outer hair cells and maintenance of normal hearing.
In 6 patients from 2 unrelated consanguineous Iraqi Jewish families with autosomal recessive deafness-76 (DFNB76; 615540), Horn et al. (2013) identified a homozygous 2-bp deletion in exon 2 of the SYNE4 gene (c.228_229delAT). Two mutant transcripts were detected: 1 that causes a frameshift and premature termination (Trp77ValfsTer16), and a second more abundant transcript that skips exon 2, resulting in a frameshift, premature termination, and a truncated protein of 51 residues. The mutation was found by homozygosity mapping followed by Sanger sequencing of genes within the interval. The heterozygous 2-bp deletion was found in 4 of 157 Iraqi Jewish controls, consistent with an allele frequency of 0.013, but was not found in 105 Israeli controls of other origins. In vitro functional expression studies showed that both truncated mutant proteins had abnormal intracellular localization within the cytoplasm rather than to the nuclear envelope. Mutation carriers had onset of progressive high frequency hearing impairment between birth and 6 years of age. The hearing loss was severe at high frequencies by adulthood.
Horn, H. F., Brownstein, Z., Lenz, D. R., Shivatzki, S., Dror, A. A., Dagan-Rosenfeld, O., Friedman, L. M., Roux, K. J., Kozlov, S., Jeang, K.-T., Frydman, M., Burke, B., Stewart, C. L., Avraham, K. B. The LINC complex is essential for hearing. J. Clin. Invest. 123: 740-750, 2013. [PubMed: 23348741] [Full Text: https://doi.org/10.1172/JCI66911]
Roux, K. J., Crisp, M. L., Liu, Q., Kim, D., Kozlov, S., Stewart, C. L., Burke, B. Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization. Proc. Nat. Acad. Sci. 106: 2194-2199, 2009. [PubMed: 19164528] [Full Text: https://doi.org/10.1073/pnas.0808602106]