* 613121

NEXILIN F-ACTIN-BINDING PROTEIN; NEXN


Alternative titles; symbols

NEXILIN, RAT, HOMOLOG OF
NEXILIN-LIKE PROTEIN; NELIN


HGNC Approved Gene Symbol: NEXN

Cytogenetic location: 1p31.1     Genomic coordinates (GRCh38): 1:77,888,624-77,943,895 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p31.1 Cardiomyopathy, dilated, 1CC 613122 AD 3
Cardiomyopathy, hypertrophic, 20 613876 AD 3

TEXT

Description

NEXN is a filamentous actin (F-actin; see 102560)-binding protein that localizes to focal contacts and may be involved in cell adhesion and migration (Ohtsuka et al., 1998; Wang et al., 2005).


Cloning and Expression

Ohtsuka et al. (1998) cloned 2 splice variants of rat nexilin, which they called b-nexilin and s-nexilin, from brain and cultured fibroblasts, respectively. The name nexilin came from the Latin word nexilis, meaning 'bound together.' Full-length b-nexilin contains an N-terminal F-actin-binding domain (ABD), followed by a spacer, a coiled-coil region, a second ABD, and a long C-terminal tail. In comparison, s-nexilin lacks the N-terminal ABD and has an insertion in the C-terminal tail. Immunofluorescence microscopy revealed that both b-nexilin and s-nexilin colocalized with F-actin at focal contacts at the ends of stress fibers. The nexilins did not localize to cell-cell junctions. Western blot analysis detected nexilin proteins with apparent molecular masses above 90 kD in rat brain, testis, and spleen and in cultured rodent fibroblasts. Neither protein was detected in liver, kidney, or epithelial cell lines. Wang et al. (2010) stated that the full-length nexilin protein contains 675 amino acids.

By sequencing clones obtained from a heart cDNA library and by EST database analysis, Zhao et al. (2001) cloned human nexilin, which they called NELIN. The deduced 493-amino acid protein contains an N-terminal FERIN-like domain, followed by an ABD and a C-terminal immunoglobulin domain. It also has 2 nuclear localization signals. Northern blot analysis detected a major 4.0-kb transcript in adult and fetal heart and skeletal muscle only. A minor 2.7-kb transcript, representing the NELIN cDNA cloned by Zhao et al. (2001), was detected in adult and fetal heart only.

Using RT-PCR, Wang et al. (2005) cloned NELIN from umbilical vein wall mRNA. The deduced protein contains 447 amino acids. Northern blot analysis detected a major transcript of about 3.0 kb in heart and skeletal muscle. Fluorescence-tagged NELIN localized predominantly to the cytoplasm of transfected HeLa cells, with some perinuclear concentration. NELIN colocalized with F-actin.

Using whole-mount antisense RNA in situ hybridization, Hassel et al. (2009) found that NEXN expression first became detectable in the developing somite and zebrafish heart tube and remained restricted to the heart and skeletal muscle throughout embryogenesis.


Gene Structure

Wang et al. (2010) noted that the NEXN gene contains 13 exons.


Mapping

By genomic sequence analysis, Zhao et al. (2001) mapped the NEXN gene to chromosome 1p32-p31.

Hassel et al. (2009) noted that the NEXN gene maps to chromosome 1p31.1.


Gene Function

Using F-actin and deletion constructs of recombinant rat nexilins in cosedimentation assays, Ohtsuka et al. (1998) showed that b-nexilin has 2 ABDs and that s-nexilin has a single ABD. The coiled-coil region and the second ABD were required for localization of b-nexilin and s-nexilin at focal contacts. Pretreatment of F-actin with myosin (see 160730) subfragment-1, which binds along the sides of F-actin, inhibited F-actin binding by b-nexilin. This inhibition was reversed by MgATP, which dissociates the actin-myosin complex. B-nexilin, but not s-nexilin, increased the viscosity of the nexilin-F-actin complex, and electron microscopy showed that the increased viscosity was due to F-actin crosslink formation by b-nexilin. The stoichiometry of nexilin-F-actin binding appeared to be 1 b-nexilin molecule per about 9 actin molecules and 1 s-nexilin molecule per about 10 actin molecules. Ohtsuka et al. (1998) concluded that the nexilins bind along the sides of F-actin, and that the second ABD of b-nexilin is engaged in F-actin crosslinking.

Wang et al. (2005) found that epitope-tagged NELIN coimmunoprecipitated with F-actin from rat PC12 cells. HeLa cells overexpressing NELIN showed increased cell migration and elevated adhesion compared with control cells.

Hassel et al. (2009) inactivated zebrafish nexilin by morpholino injection and observed development of severe heart failure. The authors found that nexilin was dispensable for early heart development, differentiation of cardiomyocytes, and expression of contractile elements, but analysis of the ultrastructure of cardiac muscle cells revealed that although the primary organization of thick and thin filaments was normal in nexilin-deficient zebrafish hearts, sarcomeric units were disrupted and frequently detached from the irregular and blurry Z discs, leaving sarcomeres in tatters. Sarcomere damage became more extensive as the embryos aged from 48 to 72 hours after fertilization, suggesting that nexilin has an essential role in the maintenance of Z disc and sarcomere integrity rather than in the primary assembly of these structures. Increasing mechanical strain aggravated Z disc damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z discs from mechanical trauma. Immunoprecipitation-western blotting assays indicated that nexilin forms a complex with alpha-actin (see 102540), beta-actin (102630), and alpha-actinin (see 102575) at the cardiac Z disc.

Hu et al. (2019) found that expression of NEXN and its antisense long noncoding RNA (lncRNA), NEXNAS1 (618370), was lower in human atherosclerotic plaques compared with healthy aortic tissue. NEXNAS1 overexpression in vascular endothelial cells increased NEXN expression, whereas knockdown of NEXNAS1 decreased NEXN expression. In vitro experiments revealed that NEXNAS1 interacted with the 5-prime flanking region of the NEXN gene. The 5-prime region of NEXNAS1 also interacted with the chromatin remodeler BAZ1A (605680). Knockdown of BAZ1A in vascular endothelial cells resulted in an open chromatin state in the 5-prime flanking region of NEXN, leading to increased NEXN expression, and this effect was enhanced by increased NEXNAS1 expression. Increased NEXNAS1 and NEXN expression suppressed the TLR4 (603030)/NF-kappa-B (see 164011) pathway, downregulated expression of inflammatory genes in endothelial cells, and reduced adhesion of monocytes to endothelial cells.


Molecular Genetics

Dilated Cardiomyopathy 1CC

Because of evidence that loss of nexilin leads to severe cardiomyopathy in zebrafish, Hassel et al. (2009) analyzed the NEXN gene in 90 patients diagnosed with idiopathic dilated cardiomyopathy (CMD) and identified heterozygosity for a 3-bp deletion (G650del; 613121.0001) in 2 patients with CMD1CC (613122). Screening of the entire NEXN coding sequence in an additional 910 CMD patients revealed the G650del mutation in 4 more patients. In addition, 2 heterozygous missense mutations were detected, Y652C in 2 patients (613121.0002) and P611T in 1 patient (613121.0003). None of the mutations were found in 1,251 age-, gender-, ethnicity- and geography-matched controls. All mutation-positive patients were screened for mutations in other known CMD-associated genes, but no mutations were identified.

Hypertrophic Cardiomyopathy 20

Wang et al. (2010) analyzed the NEXN gene in 121 unrelated Han Chinese patients with CMH who were negative for mutations in 8 common myofilament-associated genes responsible for CMH, and they identified 2 heterozygous missense mutations in 2 probands (613121.0004 and 613121.0005, respectively) that were located at highly conserved residues, segregated with disease in each family, and were not found in 192 ethnically matched controls.


Animal Model

Hu et al. (2019) found that Nexn +/- mice on an Apoe (107741) -/- background fed a Western high-fat diet had more atherosclerosis, higher levels of Tlr4, and increased expression of adhesion molecules, inflammatory cytokines, and matrix metalloproteinases compared with Nexn +/+ Apoe -/- mice. Conversely, Apoe -/- mice with Nexn overexpression had smaller atherosclerotic plaques compared with controls.


ALLELIC VARIANTS ( 5 Selected Examples):

.0001 CARDIOMYOPATHY, DILATED, 1CC

NEXN, 3-BP DEL, 1948GGA
  
RCV000041169...

In 6 patients with dilated cardiomyopathy (CMD1CC; 613122), Hassel et al. (2009) identified heterozygosity for a 3-bp deletion in the NEXN gene, resulting loss of a conserved gly650 residue (G650del). The deletion was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. One proband had a mildly affected brother who carried the deletion and an asymptomatic 33-year-old daughter, who declined further evaluation. Two probands had fathers who did not carry the deletion, and both obligate-carrier mothers had died of cardiac failure; 1 of the 2 probands also had 2 brothers who had died of cardiac failure. All G650del carriers shared an identical haplotype over a large genomic region surrounding the NEXN gene, suggesting a founder effect. Ultrastructural analysis of myocardial biopsy tissue from a G650del patient showed disruption of sarcomeric units with detached and blurry Z discs, similar to that seen in NEXN-deficient zebrafish. Ectopic expression of G650-deleted nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption. Injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.


.0002 CARDIOMYOPATHY, DILATED, 1CC

NEXN, TYR652CYS
  
RCV000000354...

In 2 patients with dilated cardiomyopathy (CMD1CC; 613121), Hassel et al. (2009) identified heterozygosity for a 1955A-G transition in the NEXN gene, resulting in a tyr652-to-cys (Y652C) substitution at a highly conserved residue. Both probands had a parent who had died of dilated cardiomyopathy; 1 proband underwent heart transplantation at age 60 years due to progressive dilated cardiomyopathy. The 2 Y652C mutation carriers shared a common haplotype that was distinct from the G650del (613121.0001)-associated haplotype, suggesting a distinct founder effect; the mutation was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. Ultrastructural analysis of myocardial biopsy tissue from a Y652C patient showed disruption of sarcomeric units with detached and blurry Z discs, similar to that seen in NEXN-deficient zebrafish. Ectopic expression of Y652C-mutated nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption. Injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.


.0003 CARDIOMYOPATHY, DILATED, 1CC

NEXN, PRO611THR
  
RCV000000355

In a patient with dilated cardiomyopathy (CMD1CC; 613121), Hassel et al. (2009) identified heterozygosity for a 1831C-A transversion in the NEXN gene, resulting in a pro611-to-thr (P611T) substitution at a highly conserved residue that was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. Ectopic expression of P611T-mutated nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption; injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.


.0004 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 20

NEXN, GLN131GLU
  
RCV000023984

In a 37-year-old Han Chinese woman with familial hypertrophic cardiomyopathy (CMH20; 613876), Wang et al. (2010) identified heterozygosity for a 391C-G transversion in exon 5 of the NEXN gene, resulting in a gln131-to-glu (Q131E) substitution at a highly conserved residue in the N-terminal actin-binding domain (ABD). The mutation was also detected in the proband's affected brother and daughter, but was not found in her unaffected daughter or 192 ethnically matched controls. Transfection studies in C2C12 cells showed that mutant nexilin accumulated in the cytoplasm and that the expressed fragment of Q131E-mutant ABD completely lost the ability to bind F-actin (see 102610). Coimmunoprecipitation assays indicated that the Q131E mutation decreased the binding of full-length NEXN to alpha-actin (102610) and abolished the interaction between the fragment of ABD and alpha-actin.


.0005 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 20

NEXN, ARG279CYS
  
RCV000023985...

In a 45-year-old Han Chinese man with familial hypertrophic cardiomyopathy (CMH20; 613876), Wang et al. (2010) identified heterozygosity for an 835C-T transition in exon 8 of the NEXN gene, resulting in an arg279-to-cys (R279C) substitution at a highly conserved residue in the coiled-coil domain. The R279C mutation was detected in the proband's affected father and brother, and was also present in his 12-year-old clinically asymptomatic daughter, but was not found in 192 ethnically matched controls. Transfection studies in C2C12 cells showed that mutant nexilin accumulated in the cytoplasm, but binding to alpha-actin (102610) was not altered.


REFERENCES

  1. Hassel, D., Dahme, T., Erdmann, J., Meder, B., Huge, A., Stoll, M., Just, S., Hess, A., Ehlermann, P. Weichenhan, D., Grimmler, M., Liptau, H., Hetzer, R., Regitz-Zagrosek, V., Fischer, C., Nurnberg, P., Schunkert, H., Katus, H. A., Rottbauer, W. Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. Nature Med. 15: 1281-1288, 2009. [PubMed: 19881492, related citations] [Full Text]

  2. Hu, Y.-W., Guo, F.-X., Xu, Y.-J., Li, P., Lu, Z.-F., McVey, D. G., Zheng, L., Wang, Q., Ye, J. H., Kang, C.-M., Wu, S.-G., Zhao, J.-J., and 12 others. Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN. J. Clin. Invest. 129: 1115-1128, 2019. [PubMed: 30589415, related citations] [Full Text]

  3. Ohtsuka, T., Nakanishi, H., Ikeda, W., Satoh, A., Momose, Y., Nishioka, H., Takai, Y. Nexilin: a novel actin filament-binding protein localized at cell-matrix adherens junction. J. Cell Biol. 143: 1227-1238, 1998. [PubMed: 9832551, images, related citations] [Full Text]

  4. Wang, H., Li, Z., Wang, J., Sun, K., Cui, Q., Song, L., Zou, Y., Wang, X., Liu, X., Hui, R., Fan, Y. Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. Am. J. Hum. Genet. 87: 687-693, 2010. [PubMed: 20970104, images, related citations] [Full Text]

  5. Wang, W., Zhang, W., Han, Y., Chen, J., Wang, Y., Zhang, Z., Hui, R. NELIN, a new F-actin associated protein, stimulates HeLa cell migration and adhesion. Biochem. Biophys. Res. Commun. 330: 1127-1131, 2005. [PubMed: 15823560, related citations] [Full Text]

  6. Zhao, Y., Wei, Y.-J., Cao, H.-Q., Ding, J.-F. Molecular cloning of NELIN, a putative human cytoskeleton regulation gene. Acta Biochim. Biophys. Sinica 33: 19-24, 2001. [PubMed: 12053183, related citations]


Bao Lige - updated : 03/27/2019
Marla J. F. O'Neill - updated : 4/6/2011
Marla J. F. O'Neill - updated : 11/17/2009
Creation Date:
Patricia A. Hartz : 11/12/2009
mgross : 03/27/2019
carol : 11/23/2016
terry : 06/11/2012
alopez : 2/3/2012
carol : 7/6/2011
wwang : 4/8/2011
terry : 4/6/2011
terry : 10/12/2010
wwang : 11/17/2009
mgross : 11/12/2009

* 613121

NEXILIN F-ACTIN-BINDING PROTEIN; NEXN


Alternative titles; symbols

NEXILIN, RAT, HOMOLOG OF
NEXILIN-LIKE PROTEIN; NELIN


HGNC Approved Gene Symbol: NEXN

Cytogenetic location: 1p31.1     Genomic coordinates (GRCh38): 1:77,888,624-77,943,895 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p31.1 Cardiomyopathy, dilated, 1CC 613122 Autosomal dominant 3
Cardiomyopathy, hypertrophic, 20 613876 Autosomal dominant 3

TEXT

Description

NEXN is a filamentous actin (F-actin; see 102560)-binding protein that localizes to focal contacts and may be involved in cell adhesion and migration (Ohtsuka et al., 1998; Wang et al., 2005).


Cloning and Expression

Ohtsuka et al. (1998) cloned 2 splice variants of rat nexilin, which they called b-nexilin and s-nexilin, from brain and cultured fibroblasts, respectively. The name nexilin came from the Latin word nexilis, meaning 'bound together.' Full-length b-nexilin contains an N-terminal F-actin-binding domain (ABD), followed by a spacer, a coiled-coil region, a second ABD, and a long C-terminal tail. In comparison, s-nexilin lacks the N-terminal ABD and has an insertion in the C-terminal tail. Immunofluorescence microscopy revealed that both b-nexilin and s-nexilin colocalized with F-actin at focal contacts at the ends of stress fibers. The nexilins did not localize to cell-cell junctions. Western blot analysis detected nexilin proteins with apparent molecular masses above 90 kD in rat brain, testis, and spleen and in cultured rodent fibroblasts. Neither protein was detected in liver, kidney, or epithelial cell lines. Wang et al. (2010) stated that the full-length nexilin protein contains 675 amino acids.

By sequencing clones obtained from a heart cDNA library and by EST database analysis, Zhao et al. (2001) cloned human nexilin, which they called NELIN. The deduced 493-amino acid protein contains an N-terminal FERIN-like domain, followed by an ABD and a C-terminal immunoglobulin domain. It also has 2 nuclear localization signals. Northern blot analysis detected a major 4.0-kb transcript in adult and fetal heart and skeletal muscle only. A minor 2.7-kb transcript, representing the NELIN cDNA cloned by Zhao et al. (2001), was detected in adult and fetal heart only.

Using RT-PCR, Wang et al. (2005) cloned NELIN from umbilical vein wall mRNA. The deduced protein contains 447 amino acids. Northern blot analysis detected a major transcript of about 3.0 kb in heart and skeletal muscle. Fluorescence-tagged NELIN localized predominantly to the cytoplasm of transfected HeLa cells, with some perinuclear concentration. NELIN colocalized with F-actin.

Using whole-mount antisense RNA in situ hybridization, Hassel et al. (2009) found that NEXN expression first became detectable in the developing somite and zebrafish heart tube and remained restricted to the heart and skeletal muscle throughout embryogenesis.


Gene Structure

Wang et al. (2010) noted that the NEXN gene contains 13 exons.


Mapping

By genomic sequence analysis, Zhao et al. (2001) mapped the NEXN gene to chromosome 1p32-p31.

Hassel et al. (2009) noted that the NEXN gene maps to chromosome 1p31.1.


Gene Function

Using F-actin and deletion constructs of recombinant rat nexilins in cosedimentation assays, Ohtsuka et al. (1998) showed that b-nexilin has 2 ABDs and that s-nexilin has a single ABD. The coiled-coil region and the second ABD were required for localization of b-nexilin and s-nexilin at focal contacts. Pretreatment of F-actin with myosin (see 160730) subfragment-1, which binds along the sides of F-actin, inhibited F-actin binding by b-nexilin. This inhibition was reversed by MgATP, which dissociates the actin-myosin complex. B-nexilin, but not s-nexilin, increased the viscosity of the nexilin-F-actin complex, and electron microscopy showed that the increased viscosity was due to F-actin crosslink formation by b-nexilin. The stoichiometry of nexilin-F-actin binding appeared to be 1 b-nexilin molecule per about 9 actin molecules and 1 s-nexilin molecule per about 10 actin molecules. Ohtsuka et al. (1998) concluded that the nexilins bind along the sides of F-actin, and that the second ABD of b-nexilin is engaged in F-actin crosslinking.

Wang et al. (2005) found that epitope-tagged NELIN coimmunoprecipitated with F-actin from rat PC12 cells. HeLa cells overexpressing NELIN showed increased cell migration and elevated adhesion compared with control cells.

Hassel et al. (2009) inactivated zebrafish nexilin by morpholino injection and observed development of severe heart failure. The authors found that nexilin was dispensable for early heart development, differentiation of cardiomyocytes, and expression of contractile elements, but analysis of the ultrastructure of cardiac muscle cells revealed that although the primary organization of thick and thin filaments was normal in nexilin-deficient zebrafish hearts, sarcomeric units were disrupted and frequently detached from the irregular and blurry Z discs, leaving sarcomeres in tatters. Sarcomere damage became more extensive as the embryos aged from 48 to 72 hours after fertilization, suggesting that nexilin has an essential role in the maintenance of Z disc and sarcomere integrity rather than in the primary assembly of these structures. Increasing mechanical strain aggravated Z disc damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z discs from mechanical trauma. Immunoprecipitation-western blotting assays indicated that nexilin forms a complex with alpha-actin (see 102540), beta-actin (102630), and alpha-actinin (see 102575) at the cardiac Z disc.

Hu et al. (2019) found that expression of NEXN and its antisense long noncoding RNA (lncRNA), NEXNAS1 (618370), was lower in human atherosclerotic plaques compared with healthy aortic tissue. NEXNAS1 overexpression in vascular endothelial cells increased NEXN expression, whereas knockdown of NEXNAS1 decreased NEXN expression. In vitro experiments revealed that NEXNAS1 interacted with the 5-prime flanking region of the NEXN gene. The 5-prime region of NEXNAS1 also interacted with the chromatin remodeler BAZ1A (605680). Knockdown of BAZ1A in vascular endothelial cells resulted in an open chromatin state in the 5-prime flanking region of NEXN, leading to increased NEXN expression, and this effect was enhanced by increased NEXNAS1 expression. Increased NEXNAS1 and NEXN expression suppressed the TLR4 (603030)/NF-kappa-B (see 164011) pathway, downregulated expression of inflammatory genes in endothelial cells, and reduced adhesion of monocytes to endothelial cells.


Molecular Genetics

Dilated Cardiomyopathy 1CC

Because of evidence that loss of nexilin leads to severe cardiomyopathy in zebrafish, Hassel et al. (2009) analyzed the NEXN gene in 90 patients diagnosed with idiopathic dilated cardiomyopathy (CMD) and identified heterozygosity for a 3-bp deletion (G650del; 613121.0001) in 2 patients with CMD1CC (613122). Screening of the entire NEXN coding sequence in an additional 910 CMD patients revealed the G650del mutation in 4 more patients. In addition, 2 heterozygous missense mutations were detected, Y652C in 2 patients (613121.0002) and P611T in 1 patient (613121.0003). None of the mutations were found in 1,251 age-, gender-, ethnicity- and geography-matched controls. All mutation-positive patients were screened for mutations in other known CMD-associated genes, but no mutations were identified.

Hypertrophic Cardiomyopathy 20

Wang et al. (2010) analyzed the NEXN gene in 121 unrelated Han Chinese patients with CMH who were negative for mutations in 8 common myofilament-associated genes responsible for CMH, and they identified 2 heterozygous missense mutations in 2 probands (613121.0004 and 613121.0005, respectively) that were located at highly conserved residues, segregated with disease in each family, and were not found in 192 ethnically matched controls.


Animal Model

Hu et al. (2019) found that Nexn +/- mice on an Apoe (107741) -/- background fed a Western high-fat diet had more atherosclerosis, higher levels of Tlr4, and increased expression of adhesion molecules, inflammatory cytokines, and matrix metalloproteinases compared with Nexn +/+ Apoe -/- mice. Conversely, Apoe -/- mice with Nexn overexpression had smaller atherosclerotic plaques compared with controls.


ALLELIC VARIANTS 5 Selected Examples):

.0001   CARDIOMYOPATHY, DILATED, 1CC

NEXN, 3-BP DEL, 1948GGA
SNP: rs397517853, ClinVar: RCV000041169, RCV000251358, RCV000470679, RCV000766521, RCV000768810, RCV000986336

In 6 patients with dilated cardiomyopathy (CMD1CC; 613122), Hassel et al. (2009) identified heterozygosity for a 3-bp deletion in the NEXN gene, resulting loss of a conserved gly650 residue (G650del). The deletion was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. One proband had a mildly affected brother who carried the deletion and an asymptomatic 33-year-old daughter, who declined further evaluation. Two probands had fathers who did not carry the deletion, and both obligate-carrier mothers had died of cardiac failure; 1 of the 2 probands also had 2 brothers who had died of cardiac failure. All G650del carriers shared an identical haplotype over a large genomic region surrounding the NEXN gene, suggesting a founder effect. Ultrastructural analysis of myocardial biopsy tissue from a G650del patient showed disruption of sarcomeric units with detached and blurry Z discs, similar to that seen in NEXN-deficient zebrafish. Ectopic expression of G650-deleted nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption. Injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.


.0002   CARDIOMYOPATHY, DILATED, 1CC

NEXN, TYR652CYS
SNP: rs137853197, gnomAD: rs137853197, ClinVar: RCV000000354, RCV000041170, RCV000183674, RCV000208290, RCV000234084, RCV000246924, RCV000491470, RCV001170736, RCV003147270

In 2 patients with dilated cardiomyopathy (CMD1CC; 613121), Hassel et al. (2009) identified heterozygosity for a 1955A-G transition in the NEXN gene, resulting in a tyr652-to-cys (Y652C) substitution at a highly conserved residue. Both probands had a parent who had died of dilated cardiomyopathy; 1 proband underwent heart transplantation at age 60 years due to progressive dilated cardiomyopathy. The 2 Y652C mutation carriers shared a common haplotype that was distinct from the G650del (613121.0001)-associated haplotype, suggesting a distinct founder effect; the mutation was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. Ultrastructural analysis of myocardial biopsy tissue from a Y652C patient showed disruption of sarcomeric units with detached and blurry Z discs, similar to that seen in NEXN-deficient zebrafish. Ectopic expression of Y652C-mutated nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption. Injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.


.0003   CARDIOMYOPATHY, DILATED, 1CC

NEXN, PRO611THR
SNP: rs137853198, ClinVar: RCV000000355

In a patient with dilated cardiomyopathy (CMD1CC; 613121), Hassel et al. (2009) identified heterozygosity for a 1831C-A transversion in the NEXN gene, resulting in a pro611-to-thr (P611T) substitution at a highly conserved residue that was not found in 1,251 age-, gender-, ethnicity- and geography-matched controls. Ectopic expression of P611T-mutated nexilin in zebrafish resulted in dilated cardiomyopathy, with markedly reduced systolic function and Z disc disruption; injection of an equal amount of wildtype nexilin had no effect on cardiac function or ultrastructure, indicating a dominant-negative effect of the mutant nexilin.


.0004   CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 20

NEXN, GLN131GLU
SNP: rs387907079, gnomAD: rs387907079, ClinVar: RCV000023984

In a 37-year-old Han Chinese woman with familial hypertrophic cardiomyopathy (CMH20; 613876), Wang et al. (2010) identified heterozygosity for a 391C-G transversion in exon 5 of the NEXN gene, resulting in a gln131-to-glu (Q131E) substitution at a highly conserved residue in the N-terminal actin-binding domain (ABD). The mutation was also detected in the proband's affected brother and daughter, but was not found in her unaffected daughter or 192 ethnically matched controls. Transfection studies in C2C12 cells showed that mutant nexilin accumulated in the cytoplasm and that the expressed fragment of Q131E-mutant ABD completely lost the ability to bind F-actin (see 102610). Coimmunoprecipitation assays indicated that the Q131E mutation decreased the binding of full-length NEXN to alpha-actin (102610) and abolished the interaction between the fragment of ABD and alpha-actin.


.0005   CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 20

NEXN, ARG279CYS
SNP: rs146245480, gnomAD: rs146245480, ClinVar: RCV000023985, RCV000041184, RCV000143936, RCV000460527, RCV000769818, RCV001719699, RCV003934850

In a 45-year-old Han Chinese man with familial hypertrophic cardiomyopathy (CMH20; 613876), Wang et al. (2010) identified heterozygosity for an 835C-T transition in exon 8 of the NEXN gene, resulting in an arg279-to-cys (R279C) substitution at a highly conserved residue in the coiled-coil domain. The R279C mutation was detected in the proband's affected father and brother, and was also present in his 12-year-old clinically asymptomatic daughter, but was not found in 192 ethnically matched controls. Transfection studies in C2C12 cells showed that mutant nexilin accumulated in the cytoplasm, but binding to alpha-actin (102610) was not altered.


REFERENCES

  1. Hassel, D., Dahme, T., Erdmann, J., Meder, B., Huge, A., Stoll, M., Just, S., Hess, A., Ehlermann, P. Weichenhan, D., Grimmler, M., Liptau, H., Hetzer, R., Regitz-Zagrosek, V., Fischer, C., Nurnberg, P., Schunkert, H., Katus, H. A., Rottbauer, W. Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. Nature Med. 15: 1281-1288, 2009. [PubMed: 19881492] [Full Text: https://doi.org/10.1038/nm.2037]

  2. Hu, Y.-W., Guo, F.-X., Xu, Y.-J., Li, P., Lu, Z.-F., McVey, D. G., Zheng, L., Wang, Q., Ye, J. H., Kang, C.-M., Wu, S.-G., Zhao, J.-J., and 12 others. Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXN. J. Clin. Invest. 129: 1115-1128, 2019. [PubMed: 30589415] [Full Text: https://doi.org/10.1172/JCI98230]

  3. Ohtsuka, T., Nakanishi, H., Ikeda, W., Satoh, A., Momose, Y., Nishioka, H., Takai, Y. Nexilin: a novel actin filament-binding protein localized at cell-matrix adherens junction. J. Cell Biol. 143: 1227-1238, 1998. [PubMed: 9832551] [Full Text: https://doi.org/10.1083/jcb.143.5.1227]

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Contributors:
Bao Lige - updated : 03/27/2019
Marla J. F. O'Neill - updated : 4/6/2011
Marla J. F. O'Neill - updated : 11/17/2009

Creation Date:
Patricia A. Hartz : 11/12/2009

Edit History:
mgross : 03/27/2019
carol : 11/23/2016
terry : 06/11/2012
alopez : 2/3/2012
carol : 7/6/2011
wwang : 4/8/2011
terry : 4/6/2011
terry : 10/12/2010
wwang : 11/17/2009
mgross : 11/12/2009