HGNC Approved Gene Symbol: MYPN
Cytogenetic location: 10q21.3 Genomic coordinates (GRCh38): 10:68,087,897-68,212,017 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q21.3 | Cardiomyopathy, dilated, 1KK | 615248 | Autosomal dominant | 3 |
| Cardiomyopathy, familial restrictive, 4 | 615248 | Autosomal dominant | 3 | |
| Cardiomyopathy, hypertrophic, 22 | 615248 | Autosomal dominant | 3 | |
| Congenital myopathy 24 | 617336 | Autosomal recessive | 3 |
MYPN is a component of the sarcomere that tethers nebulin (161650) in skeletal muscle and nebulette (605491) in cardiac muscle to alpha-actinin (see ACTN2, 102573) at the Z lines (Bang et al., 2001).
Using rabbit nebulin as bait in a yeast 2-hybrid screen of a skeletal muscle cDNA library, followed by screening and PCR of heart and skeletal muscle cDNA libraries, Bang et al. (2001) cloned MYPN. The deduced 1,320-amino acid protein has a calculated molecular mass of 145 kD. It contains 5 immunoglobulin (Ig) repeats and 6 interdomain insertions. RNA dot blot analysis of multiple human tissues detected expression restricted to adult skeletal muscle and adult and fetal heart; fetal skeletal muscle was not examined. Immunofluorescent staining revealed that rat Mypn localized at the Z line of both heart and skeletal myofibrils, and it colocalized with cardiac ankyrin repeat protein (CARP, ANKRD1; 609599) within the I band. Mypn localized to the nucleus in about 75% of isolated rat cardiac myocytes.
By genomic sequence analysis, Bang et al. (2001) mapped the MYPN gene to chromosome 10q21.1.
By yeast 2-hybrid analysis of truncation mutants and by pull-down assays, Bang et al. (2001) identified several protein-interacting domains within MYPN: a proline triplet within interdomain-3 interacted directly with the SH3 domains of nebulin and nebulette; Ig domains III, IV, and V interacted with the C terminus of ACTN2; and the N-terminal domain interacted with CARP. MYPN did not interact with any CARP truncation mutants, suggesting that this interaction requires full-length CARP. Overexpression of the N-terminal CARP-binding domain of MYPN in chick cardiac myocytes severely disrupted all sarcomeric components studied, indicating that the MYPN-CARP complex in the central I band may regulate sarcomeric integrity. Bang et al. (2001) suggested that MYPN may also link regulatory mechanisms involved in Z-line structures (via alpha-actinin and nebulin/nebulette) to those involved in muscle gene expression (via CARP).
Ma and Wang (2002) presented evidence that the PEVK segment of titin (188840), which contains numerous SH3-binding motifs, and MYPN may play signaling roles in targeting and orienting nebulin to the Z line during sarcomere assembly.
Cardiac Phenotypes
Duboscq-Bidot et al. (2008) screened 114 probands with dilated cardiomyopathy (CMD1KK; 615248) for mutations in the MYPN gene and identified 4 heterozygous mutations (see, e.g., 608517.0001-608517.0003), in 2 (3%) of 65 familial cases and 2 (4%) of 49 sporadic cases, respectively. The familial mutations segregated fully with disease in 1 pedigree and with variable penetrance in the other, and none of the mutations were found in 400 ethnically matched controls.
Purevjav et al. (2012) screened the MYPN gene in 900 unrelated patients with hypertrophic, dilated, or restrictive cardiomyopathy, and identified 15 rare sequence variants, for an overall prevalence of 1.66%. The authors noted that the estimated prevalence was relatively high compared to other disease genes reported, with 1.72% for CMD, 1.86% for CMH (CMH22; see 615248), and 1.45% for RCM (RCM4; see 615248), suggesting that MYPN is likely to be clinically important. A P1112L missense mutation (608517.0002), previously identified in a CMD patient by Duboscq-Bidot et al. (2008), was detected in a patient with CMH; another missense mutation, Y20C (608517.0004), was identified in 1 patient with CMD and another with CMH; and a nonsense mutation (Q529X; 608517.0005) was identified in 2 sibs with RCM.
Meyer et al. (2013) analyzed the MYPN and ANKRD1 (609599) genes in 255 unrelated consecutive patients with CMD and identified 2 heterozygous missense mutations in the MYPN gene (see, e.g., 608517.0006) in 2 patients, for a prevalence of 0.8%. No disease-related mutations were found in ANKRD1.
Congenital Myopathy 24
In a Japanese woman, born of consanguineous parents, with congenital myopathy-24 (CMYP24; 617336), Miyatake et al. (2017) identified a homozygous truncating mutation in the MYPN gene (608517.0007). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. Whole-exome sequencing of 54 families with nemaline myopathy identified 3 further probands (3.6%) with biallelic loss-of-function MYPN mutations (608517.0008-608517.0011). Immunostaining and Western blot analysis of patient muscle samples or myotubes showed undetectable MYPN protein, consistent with a loss of function. Patient muscle samples showed normal nebulin (NEB; 161650) and alpha-actinin (see 102573) localization, normal actin filament length, and absence of disorganized myofibrils.
In 2 unrelated South Indian patients with CMYP24, both born to consanguineous parents, Polavarapu et al. (2021) identified homozygous splicing mutations in intron 10 of the MYPN gene (608517.0012; 608517.0013). The mutations were identified by whole-exome sequencing. Both sets of parents were heterozygous for the mutations.
Miyatake et al. (2017) found that mice homozygous for a nonsense mutation in the Mypn gene (Q526X, equivalent to human Q529X, 608517.0005) had no detectable Mypn protein in skeletal muscle. Skeletal muscle from homozygous mutant mice showed no apparent abnormalities on hematoxylin and eosin and modified Gomori staining. However, electron microscopic analysis showed mild Z-line streaming and small nemaline-like bodies, suggesting mild nemaline myopathy. Notably, homozygous mutant mice did not show muscle weakness.
In a 4-generation family with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for a G-A transition in exon 16 of the MYPN gene, resulting in an arg1088-to-his (R1088H) substitution at a highly conserved residue in an Ig-1 encoding domain. The mutation segregated with disease in the family and was not found in 400 ethnically matched controls. Two of 4 affected individuals had incomplete left bundle branch block (BBB) on ECG, 1 had right BBB, and 1 had left ventricular hypertrophy; the last 2 patients displayed microvoltage as well. Left ventricular end-diastolic diameters ranged from 60 to 67 mm, with ejection fractions of 20 to 40%. Two male patients died from their cardiac disease, at ages 29 years and 55 years, and an 18-year-old female underwent cardiac transplantation. Immunofluorescence analysis of her explanted cardiac tissue demonstrated labeling of the functionally normal right ventricle that was indistinguishable from controls, whereas the dilated left ventricle showed reduced localization of myopalladin to the Z-band region.
In a 38-year-old man with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for a C-T transition in exon 17 of the MYPN gene, resulting in a pro1112-to-leu (P1112L) substitution at a highly conserved residue in an Ig-1 encoding domain. The mutation was not found in 400 ethnically matched controls. The New York Heart Association (NYHA) class II patient had a left ventricular end-diastolic diameter of 62 mm with an 11-mm interventricular septum and an ejection fraction of 38%; electrocardiogram showed incomplete left bundle branch block as well as nonsustained ventricular tachycardia. Immunofluorescence analysis of transfected rat neonate cardiomyocytes showed sarcomeric apparatus disorganization with the mutant compared to wildtype.
In a 64-year-old woman with hypertrophic cardiomyopathy (CMH22; see 615248), Purevjav et al. (2012) identified heterozygosity for a c.3481C-A transition in what they designated as exon 15 of the MYPN gene, resulting in the P1112L substitution at an evolutionarily conserved residue in the alpha-actinin (see 102575)-binding domain. The NYHA class I patient, who had no family history of cardiomyopathy, had interventricular septal and posterior wall thicknesses of 15 mm each, with an ejection fraction of 80%.
In a 58-year-old man with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for an A-G transition in exon 18 of the MYPN gene, resulting in a val1195-to-met (V1195M) substitution at a highly conserved residue in an Ig-1 encoding domain. The mutation was not found in 400 ethnically matched controls. The patient had a left ventricular end-diastolic diameter of 63 mm with an 8-mm interventricular septum and an ejection fraction of 34%; electrocardiogram showed incomplete left bundle branch block as well as left ventricular hypertrophy. Immunofluorescence analysis of transfected rat neonate cardiomyocytes showed sarcomeric apparatus disorganization with the mutant compared to wildtype.
In a 59-year-old man with hypertrophic cardiomyopathy (CMH22; see 615248) and in a 58-year-old man with dilated cardiomyopathy (CMD1KK; 615248), both of whom were sporadic patients diagnosed at age 45 years and 52 years, respectively, Purevjav et al. (2012) identified heterozygosity for a 59A-G transition in exon 2 of the MYPN gene, resulting in a tyr20-to-cys (Y20C) substitution at an evolutionarily conserved residue in the CARP (ANKRD1; 609599)-binding domain. Transgenic mice with cardiac-restricted overexpression of the Y20C mutation developed CMH and exhibited disrupted intercalated discs as well as disturbed expression of desmin (DES; 125660), desmoplakin (DSP; 125647), connexin-43 (GJA1; 121014), and vinculin (VCL; 193065). Mutant Y20C MYPN also failed to translocate to the nucleus and showed reduced CARP binding compared to wildtype in both in vitro and in vivo systems. Purevjav et al. (2012) noted that during the course of their study, the Y20C variant was described as a SNP (rs14018105) in the 1000 Genomes Pilot Database, with a low A/G genotype frequency (0.001).
In an Asian brother and sister with restrictive cardiomyopathy (RCM4; see 615248) who also showed features of hypertrophic cardiomyopathy (CMH22; see 615248), Purevjav et al. (2012) identified heterozygosity for a 1585C-T transition in exon 9 of the MYPN gene, resulting in a gln529-to-ter (Q529X) substitution predicted to cause truncation of the 3 Ig-repeats and the nebulette (NEBL; 605491)- and alpha-actinin (see 102575)-binding domains. The mutation was also found in their mother, who had aortic regurgitation without RCM, but was not found in 1,020 controls, including 450 healthy Asian individuals. Screening of more than 20 known cardiomyopathy-associated genes in both sibs revealed no other variants. The patients were diagnosed at 7 years and 8 years of age, and both exhibited mitral regurgitation; the brother also had tricuspid regurgitation and atrial fibrillation. Both sibs underwent heart transplantation, at 11 years and 9 years of age, respectively. Histologic analysis of myocardium from the brother revealed multifocally disorganized cardiomyocytes with increased side-branching and frequent side-to-side junctions along with large hyperchromatic, bizarrely shaped nuclei; transmission election microscopy (TEM) showed myofibrillar disarray, side-to-side junctions, and mitochondrial damage. Purevjav et al. (2012) noted that the overlapping histologic and TEM features of RCM and CMH were consistent with his echocardiographic features, in which a thickened interventricular septum and dilated left atrium were seen. Histology of the sister's myocardium showed scattered myocardial degeneration, hypertrophied myocytes, and small attenuated cells within the interstitial fibrosis, and TEM showed myofibrillar degeneration, swelling of the sarcotubular system, irregular spreading of Z-discs, increased tortuosity of the intercalated discs, and electron-dense material. Rat cardiomyocytes expressing Q529X mutant MYPN demonstrated disturbed myofibrillogenesis with disruption of ACTN2 (102573), desmin (DES; 125660), and CARP (609599) recruitment.
In a 33-year-old Caucasian man with severely compromised left ventricular systolic function with a reduced ejection fraction of 15% and increased end-diastolic diameter of 82 mm (CMD1KK; 615248), Meyer et al. (2013) identified heterozygosity for a 2882C-T transition in exon 13 of the MYPN gene, resulting in a pro961-to-leu (P961L) substitution at a highly conserved residue in the third immunoglobulin-like domain. Histologic analysis of a left ventricular biopsy showed significant disruption of the periodic distribution of MYPN and alpha-actinin (see 102575) in cardiac myocytes.
In a Japanese woman, born of consanguineous parents, with congenital myopathy-24 (CMYP24; 617336), Miyatake et al. (2017) identified a homozygous 1-bp deletion (c.2003delA, NM_032578.3) in the MYPN gene, resulting in a frameshift and premature termination (Asn668ThrfsTer25). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation was filtered against the dbSNP (build 135) database; it was not found in the Exome Variant Server or ExAC databases. Familial segregation studies were not performed. Transdifferentiated myotubes of the patient showed no detectable MYPN protein, consistent with a loss of function.
In a Japanese man with congenital myopathy-24 (CMYP24; 617336), Miyatake et al. (2017) identified a homozygous A-to-C transversion in intron 14 of the MYPN gene (c.3076-2A-C, NM_032578.3) resulting in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server or ExAC databases. Analysis of patient cells showed that the mutation was associated with the production of 4 different aberrant transcripts; 3 transcripts resulted in truncated proteins that might be subject to nonsense-mediated mRNA decay, and the fourth transcript resulted in an in-frame deletion predicted to cause functional impairment. Familial segregation studies were not performed. Immunostaining and Western blot analysis of patient muscle showed undetectable MYPN protein, consistent with a loss of function.
In a Japanese woman with congenital myopathy-24 (CMYP24; 617336), Miyatake et al. (2017) identified a homozygous c.1129C-T transition (c.1129C-T, NM_032578.3) in the MYPN gene, resulting in an arg377-to-ter (R377X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server, but was found at a very low frequency (1 in 66,674 alleles of a European non-Finnish population) in the ExAC database. Familial segregation studies were not performed. Immunostaining and Western blot analysis of patient muscle showed undetectable MYPN protein, consistent with a loss of function.
In a Japanese man with congenital myopathy-24 (CMYP24; 617336), Miyatake et al. (2017) identified compound heterozygous nonsense mutations in the MYPN gene: a c.3169C-T transition (c.3169C-T, NM_032578.3), resulting in an arg1057-to-ter (R1057X) substitution, and a c.3214C-T transition, resulting in an arg1072-to-ter (R1072X; 608517.0011) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the Exome Variant Server or ExAC databases. Immunostaining and Western blot analysis of patient muscle showed undetectable MYPN protein, consistent with a loss of function.
For discussion of the c.3214C-T transition (c.3214C-T, NM_032578.3) in the MYPN gene, resulting in an arg1072-to-ter (R1072X) substitution, that was found in compound heterozygous state in a patient with congenital myopathy-24 (CMYP24; 617336) by Miyatake et al. (2017), see 608517.0010.
In a man (patient 1), born of consanguineous South Indian parents, with congenital myopathy-24 (CMYP24; 617336), Polavarapu et al. (2021) identified homozygosity for a splice site mutation (c.1973+1G-C, NM_032578.4) in the MYPN gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in his parents. The mutation was not present in the gnomAD, 1000 Genomes Project, ExAC, or dbSNP databases.
In a woman (patient 2), born to consanguineous South Indian parents, with congenital myopathy-24 (CMYP24; 617336), Polavarapu et al. (2021) identified homozygosity for a splice site mutation (c.1974-2A-C, NM_032578.4) in intron 10 of the MYPN gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in her parents and unaffected brother. The mutation was not present in the gnomAD, 1000 Genomes Project, ExAC, or dbSNP databases.
Bang, M.-L., Mudry, R. E., McElhinny, A. S., Trombitas, K., Geach, A. J., Yamasaki, R., Sorimachi, H., Granzier, H., Gregorio, C. C., Labeit, S. Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies. J. Cell Biol. 153: 413-427, 2001. [PubMed: 11309420] [Full Text: https://doi.org/10.1083/jcb.153.2.413]
Duboscq-Bidot, L., Xu, P., Charron, P., Neyroud, N., Dilanian, G., Millaire, A., Bors, V., Komajda, M., Villard, E. Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. Cardiovasc. Res. 77: 118-125, 2008. [PubMed: 18006477] [Full Text: https://doi.org/10.1093/cvr/cvm015]
Ma, K., Wang, K. Interaction of nebulin SH3 domain with titin PEVK and myopalladin: implications for the signaling and assembly role of titin and nebulin. FEBS Lett. 532: 273-278, 2002. [PubMed: 12482578] [Full Text: https://doi.org/10.1016/s0014-5793(02)03655-4]
Meyer, T., Ruppert, V., Ackermann, S., Richter, A., Perrot, A., Sperling, S. R., Posch, M. G., Maisch, B., Pankuweit, S. Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy. Europ. J. Hum. Genet. 21: 294-300, 2013. [PubMed: 22892539] [Full Text: https://doi.org/10.1038/ejhg.2012.173]
Miyatake, S., Mitsuhashi, S., Hayashi, Y. K., Purevjav, E., Nishikawa, A., Koshimizu, E., Suzuki, M., Yatabe, K., Tanaka, Y., Ogata, K., Kuru, S., Shiina, M., and 11 others. Biallelic mutations in MYPN, encoding myopalladin, are associated with childhood-onset, slowly progressive nemaline myopathy. Am. J. Hum. Genet. 100: 169-178, 2017. [PubMed: 28017374] [Full Text: https://doi.org/10.1016/j.ajhg.2016.11.017]
Polavarapu, K., Bardhan, M., Anjanappa, R. M., Vengalil, S., Preethish-Kumar, V., Shingavi, L., Chawla, T., Nashi, S., Mohan, D., Arunachal, G., Geetha, T. S., Ramprasad, V., Nalini, A. Nemaline rod/cap myopathy due to novel homozygous MYPN mutations: the first report from South Asia and comprehensive literature review. J. Clin. Neurol. 17: 409-418, 2021. [PubMed: 34184449] [Full Text: https://doi.org/10.3988/jcn.2021.17.3.409]
Purevjav, E., Arimura, T., Augustin, S., Huby, A.-C., Takagi, K., Nunoda, S., Kearney, D. L., Taylor, M. D., Terasaki, F., Bos, J. M., Ommen, S. R., Shibata, H., and 14 others. Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. Hum. Molec. Genet. 21: 2039-2053, 2012. [PubMed: 22286171] [Full Text: https://doi.org/10.1093/hmg/dds022]