LDB3 – Dilated Cardiomyopathy

LDB3 encodes ZASP, a striated muscle–specific PDZ-LIM domain protein localized at the Z-disc. Initial resequencing of six DCM genes in 289 unrelated white probands with idiopathic dilated cardiomyopathy revealed common LDB3 variants at sites 10779 and 57877 suggesting a role in susceptibility to DCM, although these variants explained only a small fraction of cases (PMID:20201937). Subsequent pediatric DCM series and clinical testing in diverse cohorts further confirmed that rare LDB3 variants contribute to disease risk and may inform family management strategies (PMID:21483645; PMID:22464770).

Monogenic evidence for an autosomal recessive form of LDB3-related DCM emerged with identification of biallelic loss-of-function variants in five unrelated families. Compound heterozygous and homozygous nonsense or frameshift alleles led to early-onset severe DCM with left ventricular non-compaction or cardiomegaly, consistent across multiple probands and pedigrees (PMID:36253531). Segregation of these variants with phenotype in each family supports a recessive inheritance model.

The variant spectrum includes missense changes in cardiac-specific exons and truncating alleles. A recurrent missense change, c.566C>T (p.Ser189Leu), falls in exon 4 and affects the PDZ-binding domain of ZASP, while multiple nonsense and frameshift variants abolish the C-terminal LIM domains required for sarcomere stability.

Functional assays demonstrate that DCM-associated missense alleles impair ZASP interactions. The p.Ser189Leu and p.Thr206Ile mutations reduce binding to phosphoglucomutase 1 under stress conditions in rat cardiomyocytes, suggesting compromised energy buffering at the Z-disc (PMID:19377068). Transgenic mice expressing the human S196L mutation develop progressive dilatation, systolic dysfunction, atrioventricular block, and altered Ca^2+ and Na^+ currents, directly linking the missense change to DCM and conduction defects (PMID:20852297).

Rescue experiments in Cypher (Ldb3) knockout mice show that expression of individual isoforms can partially rescue neonatal lethality, indicating that loss of ZASP function underlies disease pathogenesis. Differential survival of mice expressing short versus long skeletal muscle isoforms underscores the requirement for both PDZ and LIM domains in cardiac muscle integrity (PMID:12499364).

Together, genetic and experimental data support a loss-of-function mechanism for LDB3 in autosomal recessive DCM. The combination of rare LoF alleles in multiple families and robust in vivo models provides a moderate to strong basis for clinical genetic testing. Key Take-home: Recessive LDB3 variants cause early-onset severe dilated cardiomyopathy, and genetic diagnosis can guide family screening and management.

References

• Annals of human genetics | 2010 | Common susceptibility variants examined for association with dilated cardiomyopathy. PMID:20201937
• European journal of human genetics : EJHG | 2023 | Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy. PMID:36253531
• 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
• The Journal of biological chemistry | 2003 | Characterization and in vivo functional analysis of splice variants of cypher. PMID:12499364

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