Alternative titles; symbols
HGNC Approved Gene Symbol: LMOD2
Cytogenetic location: 7q31.32 Genomic coordinates (GRCh38) : 7:123,655,866-123,664,290 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.32 | Cardiomyopathy, dilated, 2G | 619897 | Autosomal recessive | 3 |
LMOD2 is an actin-binding protein that regulates thin filament length in cardiac muscle (Tsukada et al., 2010).
By searching EST databases for sequences similar to TMOD (190930), Conley et al. (2001) cloned LMOD2, which they designated CLMOD. The deduced 547-amino acid protein contains a long C-terminal polyproline sequence. LMOD2 shares 89% identity with the mouse Lmod2 protein. Northern blot analysis detected a 2.7-kb transcript expressed exclusively in heart and skeletal muscle. RNA dot blot analysis showed expression only in fetal and adult heart and adult skeletal muscle.
Conley et al. (2001) determined that the LMOD2 gene contains 3 exons and spans about 10 kb. Intron 1 spans more than 5 kb.
By genomic sequence analysis, Conley et al. (2001) mapped the LMOD2 gene to chromosome 7q31-q32.
Tsukada et al. (2010) noted that proper contraction of striated muscle cells requires alignment of actin-containing thin filaments and myosin-containing thick filaments. TMOD1 caps the pointed ends of thin filaments in cardiac muscle, preventing actin polymerization and depolarization. Tsukada et al. (2010) showed that chicken Lmod2 localized to the pointed ends of thin actin filaments, was structurally similar to Tmod1, and was expressed late in heart development, after the heart had begun to beat. Furthermore, overexpression of Lmod2 in developing chicken heart displaced Tmod1 from thin filament pointed ends and caused their elongation. Deletion of the Lmod2 actin-binding domain caused the protein to became a pointed-end capping protein. The authors concluded that Lmod2 and Tmod1 act together to fine-tune thin filament length in mature heart.
In a 30-month-old girl of Mexican descent with severe dilated cardiomyopathy (CMD2G; 619897) who underwent cardiac transplantation, Ahrens-Nicklas et al. (2019) identified homozygosity for a nonsense mutation in the LMOD2 gene (W398X; 608006.0001) that segregated with disease in the family and was not found in the homozygous state in control population databases.
In 2 sisters of Vietnamese ancestry, both of whom died in infancy with severe dilated cardiomyopathy, Greenway et al. (2021) identified compound heterozygosity for a 2-bp deletion (608006.0002) and a nonsense mutation (R513X; 608006.0003) in the LMOD2 gene. Their unaffected parents were each heterozygous for one of the mutations, neither of which was present in homozygosity in public variant databases.
In 2 brothers of Egyptian ancestry, both of whom died within hours after birth with severe dilated cardiomyopathy, Yuen et al. (2022) identified homozygosity for a splice site mutation (608006.0004) in the LMOD2 gene that segregated fully with disease in the family.
In a 7-year-old boy of Mexican ancestry with dilated cardiomyopathy, who underwent cardiac transplantation at age 14 months, Lay et al. (2022) identified homozygosity for a 2-bp deletion in the LMOD2 gene. The deletion, which segregated fully with disease in the family, was present at low minor allele frequency in only heterozygous state in the gnomAD database.
In a 30-month-old girl of Mexican descent with severe dilated cardiomyopathy (CMD2G; 619897) who underwent heart transplantation at age 10 months, Ahrens-Nicklas et al. (2019) identified homozygosity for a c.1193G-A transition in the LMOD2 gene, resulting in a trp398-to-ter (W398X) substitution. Her unaffected parents were heterozygous for the mutation, and a healthy younger sister did not carry the mutation, which was not found in the homozygous state in control population databases. Western blot analysis of left ventricular tissue from the explanted heart showed no full-length or truncated LMOD2. RT-qPCR of patient heart tissue revealed a large decrease in mature LMOD2 mRNA and only a slight decrease in LMOD2 pre-mRNA levels in patient left ventricular tissue compared to an age-matched nonfailing heart, suggesting that the mutant mRNA is eliminated by nonsense-mediated decay. In addition, measurement of other thin filament components showed reduced levels of cardiac actin (102540), cardiac troponin I (TNNI3; 191044), cardiac troponin T (TNNT2; 191045), and tropomyosin (see TPM1, 191010). Expression of the homologous mouse mutation (W405X) in Lmod2 constitutive knockout mice unexpectedly reduced onset of cardiac dilation and dysfunction in the null mice, suggesting that the mutant protein, if expressed, is at least partially functional.
In 2 sisters of Vietnamese ancestry, both of whom died in infancy with severe dilated cardiomyopathy (CMD2G; 619897), Greenway et al. (2021) identified compound heterozygosity for a 2-bp deletion (c.1243_1244del) in exon 2 of the LMOD2 gene, causing a frameshift predicted to result in a premature termination codon (Leu415ValfsTer108), and a c.1537C-T transition in exon 2, resulting in an arg513-to-ter (R513X; 608006.0003) substitution. Their unaffected parents were each heterozygous for 1 of the mutations, neither of which was present in homozygosity in public variant databases.
For discussion of the c.1537C-T transition in exon 2 of the LMOD2 gene, resulting in an arg513-to-ter (R513X) substitution, that was found in compound heterozygous state in 2 sisters of Vietnamese ancestry, both of whom died in infancy with severe dilated cardiomyopathy (CMD2G; 619897), by Greenway et al. (2021), see 608006.0002.
In 2 brothers (III-3 and III-4) of Egyptian ancestry, both of whom died within hours after birth with severe dilated cardiomyopathy (CMD2G; 619897), Yuen et al. (2022) identified homozygosity for a splice site mutation (c.273+1G-A, NM_207163.2) in intron 1 of the LMOD2 gene. Their parents, who came from the same village in Egypt, and 2 healthy sibs were heterozygous for the mutation, and another healthy sib did not carry the variant. A paternal uncle had 4 children who died in infancy from unknown causes; extended family members were not available for DNA testing. RT-PCR of patient cardiac tissue failed to amplify amplicons corresponding to LMOD2 exons 1-2-3, 1-2, or 2-3. Studies using patient fibroblasts and HEK293 cells transfected with the splice site variant showed no canonical splicing of LMOD2 exons 1-2-3; rather, multiple faint bands were seen that were identified as LMOD2 gene products spliced at alternative (cryptic) splice sites. Western blot analysis revealed the absence of full-length LMOD2 in patient cardiac tissue lysate, patient fibroblasts, and HEK293 cells transfected with the splice site variant.
In a 7-year-old boy of Mexican ancestry who presented with severe dilated cardiomyopathy (CMD2G; 619897) at 9 months of age and underwent cardiac transplantation at 14 months, Lay et al. (2022) identified homozygosity for a 2-bp deletion (c.1243_1244delCT) in the LMOD2 gene, causing a frameshift predicted to result in a premature termination codon (Leu415ValfsTer108). His unaffected parents, who came from the same small town in Mexico, and 2 healthy sibs were heterozygous for the deletion, and another healthy sib did not carry the variant; DNA was unavailable from an older sister who died at age 1 year with cardiomegaly. The deletion was present at low minor allele frequency (0.0008%) in the gnomAD database.
Ahrens-Nicklas, R. C., Pappas, C. T., Farman, G. P., Mayfield, R. M., Larrinaga, T. M., Medne, L., Ritter, A., Krantz, I. D., Murali, C., Lin, K. Y., Berger, J. H., Yum, S. W., Carreon, C. K., Gregorio, C. C. Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: a novel mechanism of neonatal dilated cardiomyopathy. Sci. Adv. 5: eaax2066, 2019. [PubMed: 31517052] [Full Text: https://doi.org/10.1126/sciadv.aax2066]
Conley, C. A., Fritz-Six, K. L., Almenar-Queralt, A., Fowler, V. M. Leiomodins: larger members of the tropomodulin (Tmod) gene family. Genomics 73: 127-139, 2001. [PubMed: 11318603] [Full Text: https://doi.org/10.1006/geno.2000.6501]
Greenway, S. C., Fruitman, D., Ferrier, R., Huculak, C., Marcadier, J., Sergi, C., Bernier, F. Early death of 2 siblings related to mutations in LMOD2, a recently discovered cause of neonatal dilated cardiomyopathy. CJC Open 3: 1300-1302, 2021. [PubMed: 34888509] [Full Text: https://doi.org/10.1016/j.cjco.2021.07.017]
Lay, E., Azamian, M. S., Denfield, S. W., Dreyer, W., Spinner, J. A., Kearney, D., Zhang, L., Worley, K. C., Bi, W., Lalani, S. R. LMOD2-related dilated cardiomyopathy presenting in late infancy. Am. J. Med. Genet. 188A: 1858-1862, 2022. [PubMed: 35188328] [Full Text: https://doi.org/10.1002/ajmg.a.62699]
Tsukada, T., Pappas, C. T., Moroz, N., Antin, P. B., Kostyukova, A. S., Gregorio, C. C. Leiomodin-2 is an antagonist of tropomodulin-1 at the pointed end of the thin filaments in cardiac muscle. J. Cell Sci. 123: 3136-3145, 2010. [PubMed: 20736303] [Full Text: https://doi.org/10.1242/jcs.071837]
Yuen, M., Worgan, L., Iwanski, J., Pappas, C. T., Joshi, H., Churko, J. M., Arbuckle, S., Kirk, E. P., Zhu, Y., Roscioli, T., Gregorio, C. C., Cooper, S. T. Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant. Europ. J. Hum. Genet. 30: 450-457, 2022. [PubMed: 35082396] [Full Text: https://doi.org/10.1038/s41431-022-01043-8]