LMOD3 – Nemaline Myopathy 10

Leiomodin-3 (LMOD3) is essential for actin thin filament nucleation in skeletal muscle, and biallelic pathogenic variants cause autosomal recessive nemaline myopathy type 10 (LMOD3; Nemaline Myopathy 10). Affected individuals present with generalized hypotonia, muscle weakness, respiratory insufficiency and bulbar palsy.

In 2014, whole-exome sequencing of 21 patients from 14 unrelated families identified homozygous or compound heterozygous truncating and frameshift variants in LMOD3, which co-segregated with severe congenital myopathy and nemaline bodies on muscle biopsy (PMID:25250574). In 2023, two adult siblings with mild delayed motor milestones, prominent facial weakness and limb muscle weakness harbored a homozygous missense c.1030C>T (p.Arg344Trp) in LMOD3 that perfectly segregated with disease in the family (PMID:36893608).

The variant spectrum comprises ≥17 truncating/frameshift alleles disrupting actin‐nucleating function (e.g., c.1372C>T (p.Gln458Ter), c.704C>G (p.Ser235Ter)) and non-truncating missense changes such as p.Gly326Arg (PMID:25250574) and p.Arg344Trp (PMID:36893608). No recurrent or founder variants have been established.

Functional studies demonstrate that LMOD3 localizes to pointed ends of thin filaments and nucleates actin polymerization; loss of LMOD3 in patient muscle leads to filament shortening and disorganization, and zebrafish lmod3 knockdown reproduces nemaline pathology. Moreover, the p.Gly326Arg substitution within the conserved leucine-rich repeat domain abrogates actin binding and thin filament regulation in vitro and in vivo (PMID:25250574; PMID:37956287).

A heterozygous LMOD3 missense variant has been reported in Kleine-Levin syndrome with incomplete segregation and a neurodevelopmental presentation, but its relevance to nemaline myopathy is unsubstantiated and may reflect pleiotropy (PMID:29923248).

Integration of robust genetic segregation and concordant functional assays supports a strong autosomal recessive association between LMOD3 and nemaline myopathy type 10, informing molecular diagnosis and variant interpretation. Key take-home: biallelic loss-of-function or critical missense LMOD3 variants disrupt actin nucleation and cause AR nemaline myopathy 10.

References

• The Journal of Clinical Investigation • 2014 • Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. PMID:25250574
• Neuromuscular Disorders : NMD • 2023 • A new homozygous missense variant in LMOD3 gene causing mild nemaline myopathy with prominent facial weakness. PMID:36893608
• 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
• Journal of Sleep Research • 2019 • Kleine-Levin syndrome is associated with LMOD3 variants. PMID:29923248

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