LDB3 – Myofibrillar Myopathy 4

A heterozygous missense variant in LIM domain–binding protein 3 (LDB3) has been reported in a patient presenting with both hypertrophic cardiomyopathy and a distal myopathy consistent with myofibrillar myopathy type 4. Genetic analysis identified c.1435G>A (p.Gly479Arg) in LDB3 in a single unrelated proband, with no additional segregation data available (PMID:38992921).

Functional studies of ZASP (the protein encoded by LDB3) demonstrate that mutations within the ZASP motif disrupt its interaction with mechanosensing partners and sarcomeric components. In vitro binding assays show that the p.Ala165Val ZM–motif mutation impairs binding to Ankrd2 and α-actinin, supporting a dominant toxic effect on sarcomere stability and myofibrillar integrity (PMID:24647531).

Taken together, current evidence supports a limited clinical validity for LDB3 in myofibrillar myopathy 4, with moderate functional support but only a single reported case. Further identification of unrelated patients and segregation analyses are needed to confirm this association and inform diagnostic use.

Key take-home: LDB3 missense variants may underlie autosomal dominant myofibrillar myopathy 4, but additional replication and family studies are required for robust clinical implementation.

References

• Clinical genetics • 2024 • A rare form of LIM domain-binding protein 3 (LDB3) mutation causes hypertrophic cardiomyopathy and myofibrillar myopathy type 4. PMID:38992921
• PloS one • 2014 • ZASP interacts with the mechanosensing protein Ankrd2 and p53 in the signalling network of striated muscle. PMID:24647531

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