LMOD3 – Nemaline Myopathy

Recent evidence robustly implicates LMOD3 in the pathogenesis of nemaline myopathy, a condition characterized by muscle weakness, hypotonia, feeding difficulties, respiratory failure, and decreased fetal movements (PMID:28815944). Multiple independent case reports and cohort studies have consistently identified homozygous or compound heterozygous loss‑of‑function variants in LMOD3 in affected individuals, underscoring its critical role in muscle structure and function.

Genetic evidence supports an autosomal recessive mode of inheritance for LMOD3‑associated nemaline myopathy. Several families, including consanguineous ones, have demonstrated clear segregation of pathogenic variants with the disease phenotype (PMID:30642739). In one multi–patient study, 21 patients from 14 unrelated families were identified with disease‐causing variants, providing compelling support through both case reports and family‐based segregation analysis (PMID:25250574).

A representative pathogenic variant, c.138dup (p.Ser47fs), exemplifies the mutational spectrum observed in LMOD3. This frameshift mutation, among others identified across studies, disrupts the coding sequence by introducing a premature stop codon, thereby leading to a truncated, non–functional protein. The consistency of LoF variants across diverse cohorts reinforces the genetic etiology of the disease (PMID:32008911).

Functional studies provide strong support for the pathogenic mechanism of LMOD3 variants. Disruption of LMOD3 impairs actin filament nucleation and results in disorganized thin filament architecture as demonstrated in zebrafish knockdown models and in vitro actin binding assays (PMID:37956287). Furthermore, these experimental findings mirror the clinical observations of muscle weakness and structural abnormalities on biopsy, thereby establishing a clear genotype‑to‑phenotype correlation.

While a single study has reported LMOD3 variants in the context of Kleine‑Levin syndrome, the overwhelming body of evidence from both clinical and experimental investigations specifically supports its association with nemaline myopathy. This highlights the importance of careful phenotype–genotype correlation and suggests that LMOD3 testing should be prioritized in patients with congenital myopathy features.

In summary, the integration of extensive genetic and functional data establishes a definitive association between LMOD3 and nemaline myopathy. This evidence not only supports the utility of LMOD3 in diagnostic decision‑making but also informs genetic counseling and potential future therapies. Key take‑home message: LMOD3 evaluation is essential for the accurate diagnosis and management of nemaline myopathy.

References

• American journal of medical genetics. Part A • 2017 • Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy PMID:28815944
• Neuromuscular disorders : NMD • 2019 • Long-term follow-up and characteristic pathological findings in severe nemaline myopathy due to LMOD3 mutations PMID:30642739
• Neuromuscular disorders : NMD • 2020 • Association of fingerprint bodies with rods in a case with mutations in the LMOD3 gene PMID:32008911
• Frontiers in genetics • 2019 • Compound Heterozygosity for Novel Truncating Variants in the LMOD3 Gene as the Cause of Polyhydramnios in Two Successive Fetuses PMID:31572445
• The Journal of clinical investigation • 2014 • Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy PMID:25250574
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • A nemaline myopathy-linked mutation inhibits the actin-regulatory functions of tropomodulin and leiomodin PMID:37956287
• Neurology • 2018 • Evidence of mild founder LMOD3 mutations causing nemaline myopathy 10 in Germany and Austria PMID:30291184

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