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MESP1 is a master regulator of early cardiac development whose perturbation has been repeatedly implicated in congenital heart anomalies. Multiple independent studies have focused on the role of MESP1 in patients with congenital heart disease, reporting several rare nonsynonymous variants identified in large patient cohorts (PMID:26694203). In these investigations, patients presenting with conotruncal defects and ventricular septal defects were screened, reinforcing the gene’s importance in orchestrating cardiogenesis.
In case‑control studies involving as many as 647 probands (PMID:26694203), researchers detected six rare, nonsynonymous MESP1 variants that were absent in ethnically matched controls. Here, genetic evidence is exemplified by the recurrent identification of the variant c.139C>G (p.Pro47Ala), which has occurred in multiple independent cohorts. This variant, along with others found in distinct studies, emphasizes the gene’s contribution to the pathogenesis of complex congenital heart anomalies.
Genetic evidence is further reinforced by segregation analyses in select families which, although limited in number of additional affected relatives, support the deleterious impact of these variants. The identified alterations in MESP1, particularly those impairing the conserved helix‑loop‑helix domain, have been shown to disrupt protein‑protein interactions crucial for normal cardiac morphogenesis (PMID:26694203).
Functional assays have provided additional layers of evidence for the pathogenicity of MESP1 variants. In vitro luciferase reporter studies and loss‑of‑function models have demonstrated that specific mutations reduce transcriptional activation and disturb the interaction between MESP1 and its partners, such as E47 (PMID:24056064, PMID:28677747). Moreover, studies elucidating the MESP1‐RING1A interaction have shown that epigenetic regulatory mechanisms are impaired by pathogenic variants, further linking genotype to phenotype in congenital heart disease (PMID:36413948).
While some evidence regarding familial segregation remains modest, the convergence of genetic and functional data across diverse studies provides a coherent narrative that MESP1 mutations significantly contribute to the etiology of congenital heart disease. The disruptions in transcriptional regulation and impaired protein interactions underscore a mechanism of haploinsufficiency and dominant‑negative effects in these patients.
Key take‑home: The robust and reproducible association between MESP1 rare variants and congenital heart disease supports its clinical utility for diagnostic genetic testing and personalized cardiac care.
Gene–Disease AssociationStrongMultiple studies have identified rare, deleterious nonsynonymous variants in MESP1 in large cohorts (e.g., 647 probands [PMID:26694203]), accompanied by functional data demonstrating impaired transcriptional activation. Genetic EvidenceStrongAt least six rare variants, including c.139C>G (p.Pro47Ala) detected in independent studies ([PMID:26694203]), provide robust support; albeit segregation data is limited. Functional EvidenceModerateIn vitro luciferase assays, loss‑of‑function models, and evidence of disrupted protein-protein interactions (e.g., with E47 and RING1A) substantiate the pathogenic effect of MESP1 mutations ([PMID:24056064], [PMID:28677747], [PMID:36413948]). |