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The MAP3K7 gene: further delineation of clinical characteristics and genotype/phenotype correlations


Abstract

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7) encodes the ubiquitously expressed transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Mutationsin the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2) and cardiospondylocarpofacial syndrome (CSCF).

The fact that different mutations can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for patients with CSCF and FMD2 who carry mutations in MAP3K7.

Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect.

Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome.

Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

Abstract

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7) encodes the ubiquitously expressed transforming growth factor β (TGF-β)-activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Mutationsin the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2) and cardiospondylocarpofacial syndrome (CSCF).

The fact that different mutations can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for patients with CSCF and FMD2 who carry mutations in MAP3K7.

Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect.

Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome.

Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:MAP3K7, frontometaphyseal dysplasia type 2, cardiospondylocarpofacial syndrome, Noonan Syndrome
Language:English
Date:1 October 2022
Deposited On:11 Jul 2022 06:52
Last Modified:27 Apr 2024 01:38
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1059-7794
Additional Information:This is the peer reviewed version of the following article: van Woerden, Geeske M; Senden, Richelle; de Konink, Charlotte; Trezza, Rossella Avagliano; Baban, Anwar; Bassetti, Jennifer Alisha; van Bever, Yolande; Bird, Lynne M; van Bon, Bregje W; Brooks, Alice S; Guan, Qiaoning; Klee, Eric W; Marcelis, Carlo; Rosado, Joel Morales; Schimmenti, Lisa A; Shikany, Amy R; Terhal, Paulien A; Nicole Weaver, K; Wessels, Marja W; van Wieringen, Hester; Hurst, Anna C; Gooch, Catherine F; Steindl, Katharina; Joset, Pascal; Rauch, Anita; Tartaglia, Marco; Niceta, Marcello; Elgersma, Ype; Demirdas, Serwet (2022). The MAP3K7 gene: further delineation of clinical characteristics and genotype/phenotype correlations. Human Mutation:Epub ahead of print, which has been published in final form at https://doi.org/10.1002/humu.24425. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. (http://www.wileyauthors.com/self-archiving)
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/humu.24425
PubMed ID:35730652
  • Content: Accepted Version
  • Language: English
  • Content: Supplemental Material
  • Language: English
  • Description: Supplemental Material