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

Carine Le Goff; Clémentine Mahaut; Avinash Abhyankar; Wilfried Le Goff; Valérie Serre; Alexandra Afenjar; Anne Destrée; Maja Di Rocco; Delphine Héron; Sébastien Jacquemont; Sandrine Marlin; Marleen Simon; John Tolmie; Alain Verloes; Jean Laurent Casanova; Arnold Munnich; Valérie Cormier-Daire

doi:10.1038/ng.1016

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

Carine Le Goff, Clémentine Mahaut, Avinash Abhyankar, Wilfried Le Goff, Valérie Serre, Alexandra Afenjar, Anne Destrée, Maja Di Rocco, Delphine Héron, Sébastien Jacquemont, Sandrine Marlin, Marleen Simon, John Tolmie, Alain Verloes, Jean Laurent Casanova, Arnold Munnich, Valérie Cormier-Daire^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

76 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	85-88
Number of pages	4
Journal	Nature Genetics
Volume	44
Issue number	1
DOIs	https://doi.org/10.1038/ng.1016
Publication status	Published - 1 Jan 2012
Externally published	Yes

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Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., Destrée, A., Di Rocco, M., Héron, D., Jacquemont, S., Marlin, S., Simon, M., Tolmie, J., Verloes, A., Casanova, J. L., Munnich, A., & Cormier-Daire, V. (2012). Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nature Genetics, 44(1), 85-88. https://doi.org/10.1038/ng.1016

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title = "Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome",

abstract = "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.",

author = "{Le Goff}, Carine and Cl{\'e}mentine Mahaut and Avinash Abhyankar and {Le Goff}, Wilfried and Val{\'e}rie Serre and Alexandra Afenjar and Anne Destr{\'e}e and {Di Rocco}, Maja and Delphine H{\'e}ron and S{\'e}bastien Jacquemont and Sandrine Marlin and Marleen Simon and John Tolmie and Alain Verloes and Casanova, {Jean Laurent} and Arnold Munnich and Val{\'e}rie Cormier-Daire",

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Le Goff, C, Mahaut, C, Abhyankar, A, Le Goff, W, Serre, V, Afenjar, A, Destrée, A, Di Rocco, M, Héron, D, Jacquemont, S, Marlin, S, Simon, M, Tolmie, J, Verloes, A, Casanova, JL, Munnich, A & Cormier-Daire, V 2012, 'Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome', Nature Genetics, vol. 44, no. 1, pp. 85-88. https://doi.org/10.1038/ng.1016

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AU - Le Goff, Carine

AU - Mahaut, Clémentine

AU - Abhyankar, Avinash

AU - Le Goff, Wilfried

AU - Serre, Valérie

AU - Afenjar, Alexandra

AU - Destrée, Anne

AU - Di Rocco, Maja

AU - Héron, Delphine

AU - Jacquemont, Sébastien

AU - Marlin, Sandrine

AU - Simon, Marleen

AU - Tolmie, John

AU - Verloes, Alain

AU - Casanova, Jean Laurent

AU - Munnich, Arnold

AU - Cormier-Daire, Valérie

PY - 2012/1/1

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N2 - 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.

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

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