HGNC Approved Gene Symbol: LMOD3
Cytogenetic location: 3p14.1 Genomic coordinates (GRCh38) : 3:69,106,065-69,122,595 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p14.1 | Nemaline myopathy 10 | 616165 | Autosomal recessive | 3 |
LMOD3 localizes close to the pointed ends of sarcomeric thin filaments in striated muscle and is predicted to play a role in stabilizing these filaments (Yuen et al., 2014).
Yuen et al. (2014) cloned human LMOD3. The deduced protein has a predicted tropomyosin (see TPM1, 191010)-binding helix near the N terminus, followed by an actin-binding helix, a glutamine-rich region, a leucine-rich repeat (LRR) domain, a proline-rich region, a basic region, and a WAS protein (301000) homology-2 (WH2) domain. In addition to the actin-binding helix, the LRR and WH2 domains are also predicted to bind actin. Western blot analysis detected higher expression of LMOD3 in adult human skeletal muscle than adult human heart. LMOD3 had an apparent molecular mass of about 80 kD in human muscle tissue and primary muscle cells. In skeletal muscle, LMOD3 expression was detected at all prenatal stages examined and in adult samples at all ages examined. In cultured human myoblasts and muscle biopsies, LMOD3 was expressed upon differentiation of myoblasts into myotubes.
Yuen et al. (2014) found that both LMOD3 and LMOD2 (608006) increased the rate of actin polymerization in an in vitro actin nucleation assay in a dose-dependent manner. Both also bound alpha-tropomyosin N-terminal peptide, although LMOD2 showed a higher binding affinity than LMOD3.
Yuen et al. (2014) determined that the LMOD3 gene contains 3 coding exons.
Hartz (2014) mapped the LMOD3 gene to chromosome 3p14.1 based on an alignment of the LMOD3 sequence (GenBank AK096900) with the genomic sequence (GRCh38).
In 21 patients from 14 families with severe congenital nemaline myopathy-10 (NEM10; 616165), Yuen et al. (2014) identified homozygous or compound heterozygous mutations in the LMOD3 gene (see, e.g., 616112.0001-616112.0005). The mutations in the first 2 families were found by whole-exome sequencing; subsequent mutations were identified by direct sequencing of the LMOD3 gene in over 540 additional probands with nemaline myopathy. Almost all mutations were nonsense or frameshift and were predicted to result in a truncated protein; most skeletal muscle biopsies showed loss of LMOD3 protein, consistent with a loss of function. TMOD4 (605834) was also decreased in patient muscle biopsies. Most patients presented antenatally or at birth with severe muscle weakness, hypotonia, respiratory insufficiency, and feeding difficulties, and most died of respiratory failure in early infancy.
In 4 unrelated adolescent or adult patients with a mild form of nemaline myopathy-10 from Austria or southern Germany, Schatz et al. (2018) identified biallelic missense mutations in the LMOD3 gene. All 4 patients carried an L550F mutation (616112.0006) in homozygosity or in compound heterozygosity with a Q335R mutation (616112.0007). The mutations were identified by whole-exome sequencing or by next-generation sequencing-based panel analysis.
In 2 sisters with severe congenital nemaline myopathy-10, born to Turkish first-cousin parents, Abbott et al. (2017) identified a homozygous frameshift mutation in the LMOD3 gene (616112.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygosity in the parents. DNA from a third affected female sib was not available for testing. In addition to findings typical of NEM10, the patients had perinatal fractures.
Yuen et al. (2014) found that morpholino-mediated knockdown of zebrafish lmod3 resulted in larvae with short bodies, bent tails, and reduced tail birefringence, consistent with abnormal skeletal muscle organization. Immunostaining revealed that lmod3-morphant muscle lacked well-ordered sarcomeres and showed aberrant accumulation of the Z-disc protein alpha-actinin (see 102575), a major component of nemaline bodies. Electron microscopy confirmed abnormal skeletal muscle organization in lmod3 morphants. Behaviorally, lmod3 morphants showed reduced spontaneous coiling and touch-evoked escape responses. They also exhibited trunk muscle weakness due to reduced muscle size.
In 2 sisters, born of consanguineous Algerian parents, with severe congenital nemaline myopathy-10 (NEM10; 616165), Yuen et al. (2014) identified a homozygous 1-bp duplication (c.138dupC) in the LMOD3 gene, resulting in a frameshift and premature termination (Ser47fsTer13). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient muscle showed no LMOD3 expression, consistent with a complete loss of function. Both patients died in the neonatal period. The same homozygous mutation was subsequently found in a Belgian boy with the disorder who died at age 10 months.
Abbott et al. (2017) identified the c.138dupC mutation in 2 sibs, born to first-cousin Turkish parents, with severe NEM10. The parents were heterozygous for the mutation. DNA from another affected sib was not available for testing. The 3 sibs died at 3, 6, and 43 days of age.
In 2 Australian sisters with nemaline myopathy-10 (NEM10; 616165), Yuen et al. (2014) identified compound heterozygous mutations in the LMOD3 gene: an in-frame 3-bp deletion (c.1100_1102delACA), resulting in the deletion of residue asn367 (Asn367del), and a c.1201C-T transition, resulting in an arg401-to-ter (R401X; 616112.0003) substitution. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of 1 patient showed that both mutant proteins were expressed in skeletal muscle. These 2 sisters were the only surviving patients among the cohort of 21 individuals with LMOD3 mutations. The girls were alive at ages 4 and 10 years, suggesting that one or both mutant proteins retained some residual function and conferred a milder phenotype.
For discussion of the arg401-to-ter (R401X) mutation in the LMOD3 gene that was found in compound heterozygous state in 2 patients with nemaline myopathy-10 (NEM10; 616165) by Yuen et al. (2014), see 616112.0002.
In 5 patients from 2 families of Pakistani and Afghan origin, respectively, with nemaline myopathy-10 (NEM10; 616165), Yuen et al. (2014) identified a homozygous 2-bp deletion (c.1099_1100delAA) in the LMOD3 gene, resulting in a frameshift and premature termination (Asn367GlnfsTer11). No LMOD3 was detected in skeletal muscle by Western blot analysis, consistent with a complete loss of function. All patients died in the neonatal period or during early infancy.
In 2 Swedish brothers with nemaline myopathy-10 (NEM10; 616165), Yuen et al. (2014) identified a homozygous c.1069G-T transversion in the LMOD3 gene, resulting in a glu357-to-ter (E357X) substitution. Both patients died in early infancy.
In 4 unrelated adolescent or adult patients with a mild form of nemaline myopathy-10 (NEM10; 616165) from Austria or southern Germany, Schatz et al. (2018) identified a c.1648C-T transition (c.1648C-T, NM_198271.4) in the LMOD3 gene, resulting in a leu550-to-phe (L550F) substitution. The mutation was found in homozygosity in 2 patients and in compound heterozygous state with a c.1004A-G transition, resulting in a gln335-to-arg (Q335R; 616112.0007) in the LRR domain, in the other 2 patients. The mutations occurred at highly conserved residues and were not found in the ExAC or gnomAD databases or in an in-house database. Schatz et al. (2018) suggested that the mild phenotype might be explained by a founder effect.
For discussion of the c.1004A-G transition (c.1004A-G, NM_198271.4) in the LMOD3 gene, resulting in a gln335-to-arg (Q335R) substitution, that was found in compound heterozygous state in 2 patients with nemaline myopathy-10 (NEM10; 616165) by Schatz et al. (2018), see 616112.0006.
Abbott, M., Jain, M., Pferdehirt, R., Chen, Y., Tran, A., Duz, M. B., Seven, M., Gibs, R. A., Muzny, D., Lee, B., Marom, R., Burrage, L. C. Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy. Am. J. Med. Genet. 173A: 2789-2794, 2017. [PubMed: 28815944] [Full Text: https://doi.org/10.1002/ajmg.a.38383]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/1/2014.
Schatz, U. A, Weiss, S., Wenninger, S., Schoser, B., Muss, W. H., Bittner, R. E., Schmidt, W. M., Schossig, A. S., Rudnik-Schoneborn, S., Baumann, M. Evidence of mild founder LMOD3 mutations causing nemaline myopathy 10 in Germany and Austria. Neurology 91: e1690-e1694, 2018. [PubMed: 30291184] [Full Text: https://doi.org/10.1212/WNL.0000000000006428]
Yuen, M., Sandaradura, S. A., Dowling, J. J., Kostyukova, A. S., Moroz, N., Quinlan, K. G., Lehtokari, V.-L., Ravenscroft, G., Todd, E. J., Ceyhan-Birsoy, O., Gokhin, D. S., Maluenda, J., and 45 others. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J. Clin. Invest. 124: 4693-4708, 2014. Note: Erratum: J. Clin. Invest. 125: 456 only, 2015. [PubMed: 25250574] [Full Text: https://doi.org/10.1172/JCI75199]