Alternative titles; symbols
HGNC Approved Gene Symbol: LMOD1
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:201,896,456-201,946,548 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | ?Megacystis-microcolon-intestinal hypoperistalsis syndrome 3 | 619362 | Autosomal recessive | 3 |
Leiomodin-1 (LMOD1) is preferentially expressed in vascular and visceral smooth muscle cells and is a direct target of the serum response factor (SRF; 600589)/myocardin (MYOCD; 606127) transcriptional switch (summary by Halim et al., 2017).
Thyroid-associated ophthalmopathy (TAO) is a progressive eye condition associated with autoimmune thyroid disease (ATD), particularly Graves hyperthyroidism (275000). TAO also occurs in a small proportion of patients with Hashimoto thyroiditis (140300). It has been hypothesized that the association of TAO with ATD is due to the expression of a shared or cross-reactive antigen by thyroid and eye muscle. By screening a human thyroid cDNA expression library with sera from Hashimoto thyroiditis patients, Dong et al. (1991) identified a cDNA encoding LMOD1, which they designated D1. Northern blot analysis revealed that LMOD1 is expressed as a 3.9-kb mRNA in normal thyroid and eye orbital muscle. The predicted 572-amino acid protein has a putative membrane-spanning region and 2 types of tandemly repeated blocks. Western blot analysis of thyroid tissue showed that the LMOD1 protein has a molecular mass of 64 kD. Sera from 8 of 34 patients with autoimmune thyroid disease contained antibodies to LMOD1; all 12 normal and nonautoimmune individuals were negative.
By RT-PCR, Zhang et al. (1996) found that LMOD1, which they called 1D, was expressed in all tissues tested, with highest levels in thyroid, eye muscle, skeletal muscle, and ovary.
On the basis of sequence similarities, Sung et al. (1996) suggested that the 64-kD autoantigen of Graves disease (1D) and tropomodulin (TMOD; 190930) evolved from a common ancestral gene.
Conley et al. (2001) cloned Lmod1, which they called Smlmod, from mouse heart total RNA. The deduced 567-amino acid protein shares 82% identity with human SMLMOD, and both are about 32% identical to CLMOD (LMOD2; 608006). Both mouse and human SMLMOD have a long C-terminal polyproline sequence. Northern blot analysis of human tissues detected a major 3.9-kb transcript in heart, skeletal muscle, colon, and small intestine. RNA dot blot analysis showed SMLMOD expressed at highest levels in aorta and bladder, with lower levels in several other tissues containing smooth muscle. No expression was detected in fetal tissues.
Using immunohistochemistry, Halim et al. (2017) analyzed expression of LMOD1 in human embryos and observed expression from week 14 to 22 in the smooth muscle cell layers of the intestine and bladder, including the muscularis mucosa, blood vessels, and both muscle layers of the muscularis propria. Western blot analysis showed LMOD1 expression in human aorta, bladder, and intestine; no expression was detected in the kidney.
Conley et al. (2001) determined that the mouse and human LMOD1 genes contain 3 coding exons and span about 10 kb. Intron 1 of mouse Lmod1 spans more than 5 kb.
Conley et al. (2001) stated that the LMOD1 gene maps to chromosome 1q32.
Conley (2001) found that both Tmod and Smlmod cofractionated with tropomyosin (see 191010) in the Triton-insoluble cytoskeleton fraction of rabbit stomach smooth muscle, and both were solubilized by high salt. Immunofluorescent localization found Smlmod present along the length of actin filaments of rat intestinal smooth muscle, while Tmod stained in a punctate pattern distinct from that of actin filaments or the dense body marker, alpha-actinin (see 102575). Hypercontraction of rat intestinal smooth muscle with 10 mM Ca(2+) caused both Smlmod and Tmod to associate near alpha-actinin at the periphery of actin-rich contraction bands.
Chereau et al. (2008) described the actin-binding protein leiomodin as a strong filament nucleator in muscle cells. Leiomodin shares 2 acting-binding sites with the filament pointed end-capping protein tropomodulin (190930): a flexible N-terminal region and a leucine-rich repeat domain. Leiomodin also contains a C-terminal extension of 150 residues. The smallest fragment with strong nucleation activity included the leucine-rich repeat and C-terminal extension. The N-terminal region enhanced the nucleation activity 3-fold and recruited tropomyosin, which weakly stimulated nucleation and mediated localization of leiomodin to the middle of muscle sarcomeres. Chereau et al. (2008) found that knocking down leiomodin severely compromised sarcomere assembly in cultured muscle cells, suggesting a role for leiomodin in the nucleation of tropomyosin-decorated filaments in muscles.
After siRNA knockdown of LMOD1 in purified human intestinal smooth muscle cells (hiSMCs), Halim et al. (2017) observed a reduction of filamentous actin pelleted by ultracentrifugation. A collagen gel contraction assay showed a 40% decrease in contractile activity in hiSMCs with reduced LMOD1. Lmod1 -/- mice also showed a reduction in filamentous actin, and myography experiments showed a notable lack of tensile strength in jejunum ring segments of the mutant mice. The authors suggested that loss of LMOD1 protein expression results in compromised structural integrity and impaired contraction of visceral smooth muscle-containing tissues.
In a Dutch female infant who died at 5 days of life with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS3; 619362) and was negative for mutation in known MMIHS-associated genes, Halim et al. (2017) identified homozygosity for a nonsense mutation in the LMOD1 gene (R370X; 602715.0001) for which her unaffected consanguineous parents were heterozygous.
Using CRISPR genome editing, Halim et al. (2017) generated Lmod1 -/- mice with undetectable levels of Lmod1 in the stomach, aorta, and bladder by Western blot analysis; immunofluorescence microscopy confirmed absence of Lmod1 within smooth muscle layers of the stomach, bladder, and intestine. At 18.5 days of embryonic development, homozygous mutants displayed distention of the bladder, which in some cases was so large as to encroach upon the abdominal cavity. Histology showed early-onset thinning of the detrusor muscle of the bladder. After birth, all homozygous mutants showed gastroparesis with enlargement of the stomach as well as an enlarged urinary bladder, and some also showed hydronephrosis. Histologic analysis of postnatal mice demonstrated thinning and compaction of visceral smooth muscle layers in both stomach and bladder, along with severe loss of the transitional epithelium of the bladder. There was a significant decrease in intestinal length of the Lmod1-null mice, but the small intestine showed no overt histopathologic changes and there was no evidence of microcolon. Despite the absence of Lmod1 in smooth muscle cells of the aorta and esophagus, there was no overt histopathology of those tissues. The authors noted the similarities between the phenotype of Lmod1-null mice and the MMIHS phenotype in humans.
In a Dutch female infant who died at 5 days of life with megacystis-microcolon-intestinal hypoperistalsis syndrome-3 (MMIHS3; 619362), Halim et al. (2017) identified homozygosity for a c.1108C-T transition (c.1108C-T, NM_012134.2) in exon 2 of the LMOD1 gene, resulting in an arg370-to-ter (R370X) substitution. Her unaffected consanguineous parents were heterozygous for the mutation. RT-qPCR analysis of patient dermal fibroblasts showed significantly reduced expression of LMOD1 compared to controls, and Western blot analysis showed that LMOD1 protein was also markedly reduced compared to controls.
Chereau, D., Boczkowska, M., Skwarek-Maruszewska, A., Fujiwara, I., Hayes, D. B., Rebowski, G., Lappalainen, P., Pollard, T. D., Dominguez, R. Leiomodin is an actin filament nucleator in muscle cells. Science 320: 239-243, 2008. [PubMed: 18403713] [Full Text: https://doi.org/10.1126/science.1155313]
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]
Conley, C. A. Leiomodin and tropomodulin in smooth muscle. Am. J. Physiol. Cell Physiol. 280: C1645-C1656, 2001. [PubMed: 11350761] [Full Text: https://doi.org/10.1152/ajpcell.2001.280.6.C1645]
Dong, Q., Ludgate, M., Vassart, G. Cloning and sequencing of a novel 64-kDa autoantigen recognized by patients with autoimmune thyroid disease. J. Clin. Endocr. Metab. 72: 1375-1381, 1991. [PubMed: 2026759] [Full Text: https://doi.org/10.1210/jcem-72-6-1375]
Halim, D., Wilson, M. P., Oliver, D., Brosens, E., Verheij, J. B. G. M., Han, Y., Nanda, V., Lyu, Q., Doukas, M., Stoop, H., Brouwer, R. W. W., van IJcken, W. F. J., and 13 others. Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice. Proc. Nat. Acad. Sci. 114: E2739-E2747, 2017. [PubMed: 28292896] [Full Text: https://doi.org/10.1073/pnas.1620507114]
Sung, L. A., Fan, Y.-S., Lin, C. C. Gene assignment, expression, and homology of human tropomodulin. Genomics 34: 92-96, 1996. [PubMed: 8661028] [Full Text: https://doi.org/10.1006/geno.1996.0245]
Zhang, Z.-G., Wall, J. R., Bernard, N. F. Tissue distribution and quantitation of a gene expressing a 64-kDa antigen associated with thyroid-associated ophthalmopathy. Clin. Immun. Immunopath. 80: 236-244, 1996. [PubMed: 8811043] [Full Text: https://doi.org/10.1006/clin.1996.0119]