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

Valérie Cormier-Daire and colleagues report the identification of mutations in SMAD4 that cause Myhre syndrome, a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. All of the mutations alter a single c...

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Published in:Nature genetics Vol. 44; no. 1; pp. 85 - 88
Main 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
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.01.2012
Nature Publishing Group
Subjects:
631/208/2489/144
631/208/737
Agriculture
Animal Genetics and Genomics
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Cancer Research
Child development deviations
Codon
Complex syndromes
Cryptorchidism - genetics
Developmental disabilities
Facies
Fibroblasts - metabolism
Fundamental and applied biological sciences. Psychology
Gene Function
Gene mutations
Genes
Genetic aspects
Genetics
Genetics of eukaryotes. Biological and molecular evolution
Growth Disorders - genetics
Hand Deformities, Congenital - genetics
Health aspects
Human Genetics
Humans
Hypertrophy - genetics
Intellectual Disability - genetics
Joint Diseases - genetics
letter
Life Sciences
Medical genetics
Medical sciences
Mutation
Phosphorylation
Physiological aspects
Risk factors
Signal transduction
Smad4 Protein - genetics
Studies
Transforming growth factors
Ubiquitination
France
Homology
Smad protein
Codon
Mutation
Syndrome
Homeotic gene
ISSN:1061-4036, 1546-1718, 1546-1718
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Summary:Valérie Cormier-Daire and colleagues report the identification of mutations in SMAD4 that cause Myhre syndrome, a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. All of the mutations alter a single codon in the Mad Homology 2 domain of SMAD4. 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)-β 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-β target genes, supporting the idea of impaired TGF-β–mediated transcriptional control in individuals with Myhre syndrome.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/ng.1016