MAP3K7 Loss of Function: A New Risk Factor for Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a genetically heterogeneous cause of heart failure and sudden cardiac death. According to editorial research analyzed by Groundwork, Despite advances in genetic testing, many patients remain without a molecular diagnosis. Recent research has clarify the role of MAP3K7, a gene encoding the serine/threonine kinase TAK1, in the development of DCM.

What is MAP3K7?

MAP3K7 encodes the protein TAK1, a key regulator of cardiac homeostasis. Variants of the MAP3K7 gene have been associated with syndromic diseases, including cardiospondylocarpofacial syndrome (CSCF), which can feature DCM as a component. However, the relationship between MAP3K7 variants and DCM is more complex than previously thought.

The Role of MAP3K7 in DCM

Our research demonstrates that MAP3K7 variants can cause apparently isolated DCM, expanding the phenotypic spectrum of MAP3K7-related disorders. We compiled four orthogonal lines of human genetic evidence to support this conclusion:

1. De Novo Variation in Paediatric Cardiomyopathy: In a cohort of 117 paediatric cardiomyopathy trios from the 100,000 Genomes Project, we identified two probands with rare de novo MAP3K7 missense variants. This finding was significantly more common than expected (Bonferroni-adjusted p=0.036).
2. Common Variant Association with Adult DCM: Independent genome-wide association studies (GWAS) implicated MAP3K7 as a susceptibility locus for adult DCM. This suggests that common variants of the MAP3K7 gene may contribute to the development of DCM in adults.
3. Familial Segregation: We identified families harbouring rare MAP3K7 variants, including one with segregation in nine affected relatives. This finding supports the idea that MAP3K7 variants can be inherited in an autosomal dominant pattern.
4. Rare Variant Enrichment in DCM Cases: Rare damaging non-truncating variants were enriched in DCM cases, while truncating variants were associated with DCM in the Genomics England cohort and increased left ventricular volumes in UK Biobank. This suggests that the functional impact of MAP3K7 variants may be more important than their rarity.

The Mechanism of MAP3K7 Loss of Function

Our results suggest that DCM-associated variants reduce TAK1 kinase activity, supporting a loss-of-function mechanism consistent with CSCF-associated alleles. This implies that the pathogenic effect of MAP3K7 variants may be due to impaired TAK1 signaling, rather than a gain-of-function effect.

Implications for Diagnosis and Treatment

The discovery of MAP3K7 as a risk factor for DCM has significant implications for diagnosis and treatment. Our findings support the inclusion of MAP3K7 in DCM diagnostic pipelines, particularly in cases where a molecular diagnosis is not established. also, the identification of MAP3K7 variants may provide a target for therapeutic intervention, potentially improving outcomes for patients with DCM.

in summary, our research establishes an association between MAP3K7 loss of function variants and DCM. The phenotypic spectrum of MAP3K7-related disorders is expanded by the inclusion of apparently isolated DCM, supporting the importance of genetic testing in the diagnosis of DCM.