Alternative titles; symbols
HGNC Approved Gene Symbol: SYNE2
Cytogenetic location: 14q23.2 Genomic coordinates (GRCh38): 14:63,761,596-64,226,449 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q23.2 | Emery-Dreifuss muscular dystrophy 5, autosomal dominant | 612999 | Autosomal dominant | 3 |
By searching sequence databases for homologs of SYNE1 (608441), Apel et al. (2000) identified cDNAs encoding SYNE2. Like SYNE1, SYNE2 contains multiple spectrin repeats and a 60-amino acid C-terminal region homologous to the Drosophila protein Klarsicht. RT-PCR analysis showed low to moderate expression of 2 SYNE2 splice variants in most tissues examined, including skeletal and cardiac muscle, kidney, liver, pancreas, and placenta, and indicated that alternative splicing patterns are conserved between SYNE1 and SYNE2.
By searching sequence databases using SYNE1 as probe, followed by PCR and RACE of several cDNA libraries, Zhang et al. (2001) isolated cDNAs encoding SYNE2, which they called nesprin-2. The use of alternate initiation sites and alternative splicing results in 3 major transcripts, encoding proteins of 542 amino acids (nesprin-2-alpha), 763 amino acids (nesprin-2-beta), and 3,270 amino acids (nesprin-2-gamma), as well as several other minor variants. All 3 nesprin-2 proteins contain multiple spectrin repeats, a transmembrane domain within the C-terminal Klarsicht homology domain, and several N-glycosylation and phosphorylation sites. Nesprin-2-gamma also has a bipartite nuclear localization signal and a leucine zipper motif. Northern blot analysis detected high expression of a 2.7-kb transcript in pancreas, heart, and skeletal muscle, and widespread low expression of numerous additional transcripts ranging in size from 3.1 to 11 kb.
By genomic sequence analysis, RT-PCR, and RACE, Zhang et al. (2002) and Zhen et al. (2002) extended the sequence of SYNE2 and showed that it encodes a 6,884-amino acid protein with a calculated molecular mass of 796 kD. They identified an N-terminal actin-binding region containing 2 tandem calponin (see 600806) homology domains, as well as an extension of the spectrin repeat-containing helical rod domain. The actin-binding domain shares high homology with the corresponding domains of enaptin and calmin and 97% amino acid identity with the actin-binding domain of mouse Syne2 (Zhen et al., 2002). Zhang et al. (2002) also identified SYNE2 homologs in Drosophila and C. elegans.
By Northern dot-blot analysis, Zhen et al. (2002) detected widespread expression of SYNE2, with highest levels in kidney, liver, stomach, placenta, spleen, lymphatic nodes, and peripheral blood lymphocytes. Lowest levels were in skeletal muscle and brain. Zhen et al. (2002) generated antibody against the actin-binding domain of SYNE2 and, using fractionation and immunofluorescence, showed that SYNE2 localized to nuclear membranes with a punctate staining pattern, as well as to the nucleus, with enrichment at nucleoli. In mitotic cells, SYNE2 associated with the nuclear envelope during its breakdown and with condensed chromosomes at prometaphase, then was present throughout the cytoplasm at later mitotic stages.
By database and RACE analyses, followed by PCR and DNA sequencing, Rajgor et al. (2012) identified multiple nesprin-1 (SYNE1) and nesprin-2 variants. Both nesprin-1 and nesprin-2 underwent alternative splicing and expressed multiple tissue-specific variants generated by alternate initiation and termination. Expression analysis in human fibroblasts and U2OS cells showed that subcellular localization of these variants depended on cell type. Nesprin transcription appeared to be highly adaptable, with a feedback loop regulating variant expression, as perturbing expression of 1 transcript influenced expression of other downstream transcripts.
Using fusion proteins, Zhang et al. (2001) determined that SYNE2 requires its C-terminal transmembrane domain to localize to the nuclear envelope. When the transmembrane domain was deleted, the remaining C-terminal domain was sufficient to direct nuclear targeting.
Zhen et al. (2002) found that SYNE2 associated with F-actin filaments via its actin-binding domain in cosedimentation assays. Using fusion proteins, they showed that the spectrin repeat domains of SYNE2 associated with intracellular membranes and with vesicular structures colocalizing with beta-COP (600959).
Using yeast 2-hybrid analysis and protein pull-down assays, Libotte et al. (2005) found that the last 4 spectrin repeats at the C terminus of nesprin-2 bound directly to a C-terminal region common to lamin isoforms A and C, which are both encoded by the LMNA gene (150330). Knockdown studies with human cell lines revealed that lamin A/C was required for nesprin-2 nuclear envelope localization. A C-terminal region of nesprin-2 also bound emerin (EMD; 300384), and knockdown of nesprin-2 in COS-7 cells caused redistribution of emerin away from the nuclear envelope.
Zhen et al. (2002) and Zhang et al. (2002) determined that the SYNE2 gene contains 115 exons and spans approximately 370 kb.
By FISH, Zhang et al. (2001) mapped the SYNE2 gene to chromosome 14q23.
In a father and his 2 children with Emery-Dreifuss muscular dystrophy (EDMD5; 612999), Zhang et al. (2007) identified a heterozygous mutation in the SYNE2 gene (T89M; 608442.0001). In an unrelated family, an affected woman was heterozygous for the T89M mutation. Patient fibroblasts and muscle cells showed loss of nuclear envelope integrity with mislocalization of LMNA (150330) and emerin (EMD; 300384). Immunofluorescence studies showed loss of SYNE2 expression in the nuclear envelope and mitochondria of patient fibroblasts. The same changes were observed in fibroblasts from patients with other genetic forms of EDMD, indicating that loss of nesprin is a characteristic of all forms of EDMD. RNA interference of SYNE2 recapitulated the nuclear defects membrane defects and changes in the organization of intranuclear heterochromatin observed in patient cells. Overall, the findings showed the importance of the nesprin/emerin/lamin complex in the maintenance of nuclear stability and suggested that changes in the binding stoichiometry of these proteins is a feature of EDMD. Zhang et al. (2007) concluded that the disorder is caused in part by uncoupling of the nucleoskeleton and cytoskeleton.
Zhang et al. (2009) showed that Sun1 (607723) and Sun2 (613569) double-knockout (Sun1/2 DKO) mice and Syne1 and Syne2 double-knockout (Syne1/2 DKO) mice had similar defects in brain development. Sun1/2 DKO and Syne1/2 DKO brains were small and showed defective laminary structures in many brain regions. Examination of neocortex revealed failure of radial neuronal migration, but not tangential migration of interneurons, in both Sun1/2 DKO and Syne1/2 DKO mice. Intracellular movement of nuclei is a prerequisite for proper neuron migration and development, and Zhang et al. (2009) showed that Sun1 and Sun2 anchored Syne2 to the nuclear envelope, while Syne1 and Syne2 connected the nuclear envelope to the microtubule network, permitting nuclear movement. Syne2 single-knockout mice exhibited defects in learning a T-maze and were hyperactive in a new environment, but they had no significant defects in balance or locomotion. Zhang et al. (2009) concluded that a complex made up of SUN1, SUN2, SYNE1, and SYNE2 is required for neuronal nuclear movement and for neuronal migration and development.
Maddox et al. (2015) mapped the mouse spontaneous mutation cpfl8 (cone photoreceptor function loss-8) to chromosome 12 and showed that cpfl8 cosegregated with a nonsense mutation (c.13978C-T, Q4660X) in the Syne2 gene. The reduced cone electroretinogram in cpfl8 was found to be due to a significant reduction in cone photoreceptors. Longitudinal studies of the early postnatal retina indicated that the cone photoreceptors failed to develop properly, rod photoreceptors mislocalized to the inner nuclear layer, and both rods and cones underwent apoptosis prematurely. In addition, migration defects of secondary neurons occurred, and ectopic Mueller cell bodies were found in the outer nuclear layer early in postnatal development. Maddox et al. (2015) concluded that SYNE2 is important for normal retinal development.
In a father and his 2 children with Emery-Dreifuss muscular dystrophy (EDMD5; 612999), Zhang et al. (2007) identified a heterozygous 466C-T transition in exon 3 of the SYNE2 gene, resulting in a thr89-to-met (T89M) substitution in the first spectrin repeat. The father had general weakness since age 37 years, ptosis, increased serum creatine kinase, and left ventricular hypertrophy. His daughter had transient cardiac arrhythmia at age 10 to 14 years, and his son had limb weakness and winged scapulae at age 8 years, minor respiratory insufficiency, but no cardiac involvement. In an unrelated family with EDMD5, an affected woman was heterozygous for the T89M mutation and her affected son was heterozygous for T89M and a variant in the SYNE1 gene (V572L; 608441.0009), which was also present in heterozygosity in the unaffected father, calling into question the pathogenicity of the SYNE1 V572L variant. The mother had a history of muscle weakness and died at 30 years of age from cardiomyopathy, and her son had muscular dystrophy combined with severe dilated cardiomyopathy requiring heart transplant at age 26. The T89M mutation was not found in 384 control alleles. In vitro functional expression assays showed no change in binding of the SYNE2 T89M protein to emerin (EMD; 300384), but patient fibroblasts and muscle cells showed decreased localization of EMD, LMNA (150330), and SYNE2 to the nuclear envelope, impaired binding interactions of these 3 proteins, and disruptions in the organization of intranuclear heterochromatin.
Apel, E. D., Lewis, R. M., Grady, R. M., Sanes, J. R. Syne-1, a dystrophin- and Klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction. J. Biol. Chem. 275: 31986-31995, 2000. [PubMed: 10878022] [Full Text: https://doi.org/10.1074/jbc.M004775200]
Libotte, T., Zaim, H., Abraham, S., Padmakumar, V. C., Schneider, M., Lu, W., Munck, M., Hutchison, C., Wehnert, M., Fahrenkrog, B., Sauder, U., Aebi, U., Noegel, A. A., Karakesisoglou, I. Lamin A/C-dependent localization of nesprin-2, a giant scaffolder at the nuclear envelope. Molec. Biol. Cell 16: 3411-3424, 2005. [PubMed: 15843432] [Full Text: https://doi.org/10.1091/mbc.e04-11-1009]
Maddox, D. M., Collin, G. B., Ikeda, A., Pratt, C. H., Ikeda, S., Johnson, B. A., Hurd, R. E., Shopland, L. S., Naggert, J. K., Chang, B., Krebs, M. P., Nishina, P. M. A mutation in Syne2 causes early retinal defects in photoreceptors, secondary neurons, and Mueller glia. Invest. Ophthal. Vis. Sci. 56: 3776-3787, 2015. [PubMed: 26066746] [Full Text: https://doi.org/10.1167/iovs.14-16047]
Rajgor, D., Mellad, J. A., Autore, F., Zhang, Q., Shanahan, C. M. Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds. PLoS One 7: e40098, 2012. Note: Electronic Article. [PubMed: 22768332] [Full Text: https://doi.org/10.1371/journal.pone.0040098]
Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., Shanahan, C. M. Nesprin-1 and -2 are involved in the pathogenesis of Emery-Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum. Molec. Genet. 16: 2816-2833, 2007. [PubMed: 17761684] [Full Text: https://doi.org/10.1093/hmg/ddm238]
Zhang, Q., Ragnauth, C., Greener, M. J., Shanahan, C. M., Roberts, R. G. The nesprins are giant actin-binding proteins, orthologous to Drosophila melanogaster muscle protein MSP-300. Genomics 80: 473-481, 2002. [PubMed: 12408964]
Zhang, Q., Skepper, J. N., Yang, F., Davies, J. D., Hegyi, L., Roberts, R. G., Weissberg, P. L., Ellis, J. A., Shanahan, C. M. Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues. J. Cell Sci. 114: 4485-4498, 2001. [PubMed: 11792814] [Full Text: https://doi.org/10.1242/jcs.114.24.4485]
Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M. SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice. Neuron 64: 173-187, 2009. [PubMed: 19874786] [Full Text: https://doi.org/10.1016/j.neuron.2009.08.018]
Zhen, Y.-Y., Libotte, T., Munck, M., Noegel, A. A., Korenbaum, E. NUANCE, a giant protein connecting the nucleus and actin cytoskeleton. J. Cell Sci. 115: 3207-3222, 2002. [PubMed: 12118075] [Full Text: https://doi.org/10.1242/jcs.115.15.3207]