Friday 30 December 2011
Myhre syndrome is a rare disorder characterized by mental retardation, dysmorphic facial features, including microcephaly, midface hypoplasia, prognathism, and blepharophimosis, as well as typical skeletal anomalies, including short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. All reported cases have been sporadic
SMAD4 was a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP signaling pathway) and transforming growth factor (TGF)-β signaling (TGFB signaling pathway).
The SMAD4 mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519. It causes a defect in SMAD4 ubiquitination in fibroblasts from affected individuals.
It is associated with a decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.
Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. 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. Nat Genet. 2011 Dec 11;44(1):85-8. PMID: 22158539