BoneKEy Reports | BoneKEy Watch

Genetic basis of Myhre syndrome

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DOI:10.1038/bonekey.2012.29

Genetic analysis of 11 individuals diagnosed with Myhre syndrome, a disorder of development that leads to a short but muscular build, small hands and feet, facial abnormalities, cognitive problems and deafness later in life, has revealed a possible association with mutations in SMAD4 (mothers-against-DPP homolog 4).

This mutation is known to cause some cases of colorectal and pancreatic cancers, mediated by a loss of sensitivity to transforming growth factor (TGF-β) signaling. The gene also plays a central role in the bone morphogenetic pathway (BMP).

Three distinct SMAD4 mutations were identified; all were missense mutations that affected the Ile500 codon and were within the part of the gene that encodes the Mad homology 3 domain, close to the site of monoubiquitination at Lys519. SMAD4 ubiquitination in the fibroblasts of the subjects with Myhre syndrome was defective. TGF-β downstream target genes also showed reduced expression, suggesting that TGF-β was disrupting transcriptional control.

Editor's comment: The finding that SMAD4 mutations in the MH2 domain cause Myhre syndrome, a developmental disorder with skeletal phenotypes, raises the interesting question whether SMAD4 mutations at different sites, or under different cellular contexts, or in different tissues, are the foundation of several different phenotypes.

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