MESP1 and Ventricular Septal Defect

This summary reviews the evidence linking mutations in MESP1 (HGNC:29658) to ventricular septal defect (MONDO_0002070). Multiple independent studies have evaluated patients with congenital heart defects and identified rare, nonsynonymous variants in MESP1. In one large study, six rare variants were discovered in 647 patients, including a loss‐of‐function frameshift mutation that is absent in ethnically matched controls (PMID:26694203). This observation supports a significant association between MESP1 abnormalities and cardiac malformations, particularly involving the ventricular septum.

Genetic evidence is bolstered by the recurrence of specific MESP1 variants across distinct patient cohorts. For instance, the variant c.209G>A (p.Gly70Asp) has been repeatedly observed in independent investigations, and additional variants such as c.139C>G (p.Pro47Ala) have been reported. Although detailed familial segregation data are sparse, the identification of these variants in unrelated probands and the occasional documentation of segregation within families suggest a dominant effect underlying the observed cardiac phenotypes (PMID:26694203).

The inheritance pattern inferred from these studies is consistent with an autosomal dominant model. De novo events and familial studies point toward a dominant mechanism in which a single mutated allele can predispose to developmental abnormalities of the heart. While the count of additional affected relatives is not robustly quantified across the studies, the overall recurrence of variants supports a high penetrance of the pathogenic alleles in affected individuals.

In addition to the genetic findings, robust functional assays have enhanced our understanding of the pathogenic mechanism. Experimental evidence from luciferase reporter assays and protein interaction studies demonstrate that pathogenic variants, including the recurrent c.209G>A (p.Gly70Asp), markedly impair MESP1 transcriptional activity. These studies, which include both in vitro and in vivo models, indicate that the deleterious variants disrupt the protein-protein interactions essential for normal cardiac mesoderm specification and subsequent heart formation (PMID:24056064; PMID:36413948).

Further functional experiments reveal that the loss‐of‐function mutations within conserved domains of MESP1 yield substantial reductions in transcriptional activation. These deficits correlate with the developmental defects observed in patients and are supported by animal model studies that recapitulate the clinical cardiac defects. The convergence of genetic and experimental data reinforces the notion that altered MESP1 function is a critical contributor to the etiology of ventricular septal defect.

In conclusion, the integration of multi‐patient genetic analyses with comprehensive functional assessments provides strong evidence for a causal link between MESP1 mutations and ventricular septal defect. The association is supported by recurrent, rare variants and consistent experimental findings, underscoring the gene’s clinical utility for diagnostic decision‑making. Key take‑home message: MESP1 mutation status should be considered in the diagnostic workup for patients with congenital heart defects, particularly those presenting with ventricular septal defects.

References

• Human Mutation | 2016 | MESP1 Mutations in Patients with Congenital Heart Defects PMID:26694203
• European Journal of Medical Genetics | 2013 | Mutational analysis of the human MESP1 gene in patients with congenital heart disease reveals a highly variable sequence in exon 1 PMID:24056064
• Molecular Medicine Reports | 2017 | MESP1 loss‐of‐function mutation contributes to double outlet right ventricle PMID:28677747
• Developmental Cell | 2022 | Essential role of MESP1-RING1A complex in cardiac differentiation PMID:36413948

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