LDB3 – Familial Dilated Cardiomyopathy

LDB3 encodes the striated muscle PDZ-LIM protein ZASP, which localizes to the Z-disc and maintains sarcomeric integrity. Heterozygous LDB3 variants have been implicated in familial dilated cardiomyopathy (FDC), a primary myocardial disease characterized by left ventricular dilation and systolic dysfunction (MONDO:0016333). Clinically, FDC exhibits autosomal dominant inheritance with variable penetrance and age of onset.

In a cohort of 313 patients with FDC or idiopathic DCM, bidirectional sequencing of LDB3 identified two unique protein-altering variants in three unrelated probands (1.0% of cases), absent in 253 controls, supporting a role in FDC ([PMID:19412328]). No segregation data were numerically specified, but family follow-up was performed. The most recurrent variant was c.1111G>A (p.Ala371Thr).

Functional analyses of LDB3 demonstrate critical isoform-specific roles: rescue of neonatal lethality in Cypher-null mice by expression of either short or long skeletal muscle isoforms confirms an essential structural function at the Z-disc ([PMID:12499364]).

Yeast two-hybrid and co-immunoprecipitation studies revealed that DCM-associated missense mutations in exons 4 and 10 (e.g., c.566C>T (p.Ser189Leu) and c.617C>T (p.Thr206Ile)) impair binding to phosphoglucomutase 1, suggesting disruption of metabolic anchoring at the Z-disc under stress conditions ([PMID:19377068]).

A transgenic mouse model expressing the exon 4 S196L mutation (c.566C>T (p.Ser189Leu)) developed age-dependent DCM and conduction defects, with altered L-type Ca2+ and Na+ currents, linking structural mutation to electrical dysfunction ([PMID:20852297]).

Recent identification of biallelic loss-of-function LDB3 variants in five unrelated families causing early-onset severe DCM further supports a loss-of-function mechanism, with Z-disc ultrastructural disorganization reminiscent of knockout phenotypes ([PMID:36253531]). Although these recessive cases are outside the dominant FDC spectrum, they underscore essential LDB3 dosage sensitivity.

Integrating genetic and experimental data, LDB3 variants disrupt Z-disc integrity and cardiac electrophysiology via impaired protein interactions and structural support. Additional evidence from muscle and cardiac splicing regulators expands the pathogenic network but exceeds ClinGen scoring limits. Key take-home: LDB3 screening informs diagnosis of dominantly inherited familial DCM and guides management of structural and conduction phenotypes.

References

• Clinical and translational science • 2008 • Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. PMID:19412328
• The Journal of biological chemistry • 2003 • Characterization and in vivo functional analysis of splice variants of cypher. PMID:12499364
• Cardiovascular research • 2009 • Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy. PMID:19377068
• Circulation. Arrhythmia and electrophysiology • 2010 • A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. PMID:20852297
• European journal of human genetics : EJHG • 2023 • Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy. PMID:36253531

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