Genetic and Myhre syndrome
Myhre syndrome
First described in 1981 by Myhre, Ruvalcaba and Graham, the Myhre syndrome is characterized by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism, short philtrum), thick skin, generalized muscle hypertrophy and restricted joint mobility.[1]
Myhre syndrome is a well-defined disorder characterized by preand postnatal short stature, brachydactyly, facial dysmorphism (short palpebral fissures, maxillary hypoplasia, prognathism and short philtrum), thick skin, generalized muscle hypertrophy and restricted joint mobility. Deafness that is of mixed conductive and sensory types is consistently observed in older individuals with this syndrome. Other features include developmental delay with mental retardation and/or behavioral disturbance, cardiac defects, cryptorchidism and bone anomalies. Skeletal manifestations include thickened calvarium, cone-shaped epiphyses, shortened tubular bones, hypoplastic iliac wings, broad ribs and large vertebrae with short and large pedicles.[2]
Genetic and Myhre syndrome
Mutations in the SMAD4 gene cause Myhre syndrome.[3]. SMAD4 encodes a protein belonging to the eight-member family of SMADs, which is divided into three functional classes: the receptorregulated SMADs (R-SMADs: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8), the co-mediator SMAD (SMAD4) and the inhibitory SMADs (SMAD6 and SMAD7). SMAD2 and SMAD3 respond to TGF-β and activin, and SMAD1, SMAD5 and SMAD8 function in BMP signaling pathways. After being activated, receptor-regulated SMADs form heterodimers with SMAD4 and translocate into the nucleus to induce or repress the expression of TGF-β and BMP target genes.[4]
Some researchers believe that the SMAD4 gene mutations that cause Myhre syndrome impair the ability of the SMAD4 protein to attach (bind) properly with the other proteins involved in the signaling pathway. Other studies have suggested that these mutations result in an abnormally stable SMAD4 protein that remains active in the cell longer. Changes in SMAD4 binding or availability may result in abnormal signaling in many cell types, which affects development of several body systems and leads to the signs and symptoms of Myhre syndrome.[5][6]
References
References
- ^ Myhre SA, Ruvalcaba RH and Graham CB. A new growth deficiency syndrome. Clin Genet 1981: 20: 1-5.
- ^ Burglen, L. et al. Myhre syndrome: new reports, review, and differential diagnosis. J. Med. Genet. 40, 546–551 (2003).
- ^ Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, et al. Novel SMAD4 mutation causing Myhre syndrome. American Journal of Medical Genetics Part A. 2014;164(7):1835-40.
- ^ Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, et al. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nature genetics. 2012;44(1):85-8.
- ^ Ross, S. & Hill, C.S. How the Smads regulate transcription. Int. J. Biochem. Cell Biol. 40, 383–408 (2008).
- ^ Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).