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Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

Authors: Le Goff, Carine  Mahaut, Clémentine  Abhyankar, Avinash  Le Goff, Wilfried  Serre, Valérie  Afenjar, Alexandra  Destrée, Anne  di Rocco, Maja  Héron, Delphine  Jacquemont, Sébastien  Marlin, Sandrine  Simon, Marleen  Tolmie, John  Verloes, Alain  Casanova, Jean-Laurent  Munnich, Arnold  Cormier-Daire, Valérie 
Citation: Le Goff C, etal., Nat Genet. 2011 Dec 11;44(1):85-8. doi: 10.1038/ng.1016.
Pubmed: (View Article at PubMed) PMID:22158539
DOI: Full-text: DOI:10.1038/ng.1016

Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-ß signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-ß target genes, supporting the idea of impaired TGF-ß-mediated transcriptional control in individuals with Myhre syndrome.

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CRRD Object Information
CRRD ID: 12880042
Created: 2017-05-02
Species: All species
Last Modified: 2017-05-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.