current
NEXN:c.1955A>G (p.Tyr652Cys) AND Dilated cardiomyopathy 1CC
current
classified by single submitter
Pathogenic
germline
human
not provided
curation
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.
19881492
NEXN:c.1955A>G (p.Tyr652Cys)
0.000084317032
c.1955A>G
LRG_442t1:c.1955A>G
NM_144573.3:c.1955A>G
LRG_442:g.59242A>G
NG_016625.1:g.59242A>G
NC_000001.10:g.78408441A>G
NP_653174.3:p.Tyr652Cys
NM_144573.3:EXON 13
missense
Y652C
TYR652CYS
1p31.1
nexilin (F actin binding protein)
NEXN
Dilated cardiomyopathy 1CC
CMD1CC
Nonsyndromic isolated dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction, a reduction in the myocardial force of contraction. DCM usually presents with any one of the following: Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion). Arrhythmias and/or conduction system disease. Thromboembolic disease (from left ventricular mural thrombus) including stroke .
Variable
1-5 / 10 000
20301486
current
Pathogenic
germline
human
not provided
curation
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.
19881492
NEXN, TYR652CYS
TYR652CYS
NEXN
CARDIOMYOPATHY, DILATED, 1CC