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


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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Figure 1: Clinical and radiological manifestations of individuals with Myhre syndrome.
Figure 2: Functional consequences of SMAD4 mutations in fibroblasts from individuals with Myhre syndrome.
Figure 3: Levels of phosphorylated SMAD proteins in skin fibroblasts from individuals with Myhre syndrome and age- and passage-matched controls.
Figure 4: Cellular localization of phosphorylated SMAD proteins.
Figure 5: Expression analysis of TGF-β– and BMP-driven target genes in fibroblasts from control and case subjects.


  1. 1

    Myhre, S.A., Ruvalcaba, H.A. & Graham, C.B. A new growth deficiency syndrome. Clin. Genet. 20, 1–5 (1981).

    CAS  Article  Google Scholar 

  2. 2

    Burglen, L. et al. Myhre syndrome: new reports, review, and differential diagnosis. J. Med. Genet. 40, 546–551 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Loeys, B.L. et al. Mutations in fibrillin-1cause congenital scleroderma: stiff skin syndrome. Sci. Transl. Med. 2, 23ra20 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Faivre, L. et al. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am. J. Med. Genet. 123, 204–207 (2003).

    Article  Google Scholar 

  5. 5

    Le Goff, C. et al. Mutations in the TGF-β binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am. J. Hum. Genet. 89, 7–14 (2011).

    CAS  Article  Google Scholar 

  6. 6

    Dagoneau, N. et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am. J. Hum. Genet. 75, 801–806 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Le Goff, C. et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation. Nat. Genet. 40, 1119–1123 (2008).

    CAS  Article  Google Scholar 

  8. 8

    Allali, S. et al. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia. J. Med. Genet. 48, 417–421 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Faivre, L. et al. In-frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J. Med. Genet. 40, 34–36 (2003).

    CAS  Article  Google Scholar 

  10. 10

    Ross, S. & Hill, C.S. How the Smads regulate transcription. Int. J. Biochem. Cell Biol. 40, 383–408 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    CAS  Article  Google Scholar 

  12. 12

    Sirard, C. et al. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later anterior development of the mouse embryo. Genes Dev. 12, 107–119 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Zhang, J. et al. Smad4 is required for the normal organization of the cartilage growth plate. Dev. Biol. 284, 311–322 (2005).

    CAS  Article  Google Scholar 

  14. 14

    Yang, S.M. et al. Chondrocyte- specific Smad4 gene conditional knockout results in hearing loss and inner ear malformation in mice. Dev. Dyn. 238, 1897–1908 (2009).

    CAS  Article  Google Scholar 

  15. 15

    Tan, X. et al. Smad4 is required for maintaining normal murine postnatal bone homeostasis. J. Cell Sci. 120, 2162–2170 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Howe, J.R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Schutte, M. et al. DPC4 gene in various tumor types. Cancer Res. 56, 2527–2530 (1996).

    CAS  PubMed  Google Scholar 

  18. 18

    Hahn, S.A. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Sunamura, M. et al. Gene therapy for pancreatic cancer based on genetic characterization of the disease. J. Hepatobiliary Pancreat. Surg. 9, 32–38 (2002).

    Article  Google Scholar 

  20. 20

    Kurokawa, M. et al. The oncoprotein Evi-1 repress TGF-β signaling by inhibiting Smad3. Nature 394, 92–96 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Xu, J. & Attisano, L. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor β signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA 97, 4820–4825 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Byun, M. et al. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J. Exp. Med. 207, 2307–2312 (2010).

    CAS  Article  Google Scholar 

  23. 23

    Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    CAS  Article  Google Scholar 

  24. 24

    McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    CAS  Article  Google Scholar 

  25. 25

    Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  26. 26

    Larrede, S. et al. Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler. Thromb. Vasc. Biol. 29, 1930–1936 (2009).

    CAS  Article  Google Scholar 

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We are grateful to the individuals with Myhre syndrome and their families for their participation in this study. We also thank the following physicians for the management of the affected individuals: D. Doummar, R. McGowan, P. Picco and M. Whiteford. This research was supported by the French National Research Agency (ANR; R09183KS to V.C.-D.).

Author information




C.L.G. designed the experiments, analyzed the exome sequencing data, performed protein blot analysis and wrote the manuscript. C.M. performed Sanger sequencing analysis. A. Abhyankar and J.-L.C. performed exome capture. W.L.G. performed quantitative RT-PCR analysis. V.S. performed three-dimensional structure analysis. A. Afenjar, A.D., M.d.R., D.H., S.J., S.M., M.S., J.T. and A.V. provided clinical data. A.M. wrote the manuscript. V.C.-D. provided clinical data, analyzed the exome sequencing data, oversaw all aspects of the research and wrote the manuscript.

Corresponding author

Correspondence to Valérie Cormier-Daire.

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The authors declare no competing financial interests.

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Le Goff, C., Mahaut, C., Abhyankar, A. et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet 44, 85–88 (2012).

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