Molecular Genetics of Myhre Syndrome


Myhre syndrome (MIM 139210) is a rare autosomal‐dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life‐threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011, SMAD4 (SMAD family member 4) has been identified as the disease‐causing gene. All mutations identified so far are de novo heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF‐β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of SMAD4 mutations during development will decipher new regulatory network related to TGF‐β/BMP signalling.

Key Concepts

  • Myhre syndrome is a rare genetic condition of autosomal‐dominant inheritance due to SMAD4 mutations affecting Arg496 or Ile500 residues.
  • Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility.
  • Myhre syndrome is associated to a risk of early death due to possibly life‐threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis).
  • Similar to mothers against decapentaplegic family member 4 (SMAD4) encodes the common partner SMAD of the eight‐member family of SMAD proteins.
  • SMAD4 aggregates into heterotrimer with the receptor‐regulated SMADs (R‐SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF‐β, activin or BMP receptor pathways.
  • The SMAD4 mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes.
  • Germline heterozygous mutations in SMAD4 are known to cause juvenile polyposis syndrome (JPS) and JPS‐hereditary hemorrhagic telangiectasia.
  • The SMAD4 mutations observed in JPS and JPS‐HHT include nonsense, missense, splice‐site changes and deletions, consistent with a loss‐of‐function mechanism.
  • Increased tumoural risk has not been observed so far in Myhre syndrome.
  • The development of tissue‐specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes.

Keywords: development; life‐threatening complications; SMAD4; TGB/BMP; ossification

Figure 1. Radiological features of Myhre syndrome.
Figure 2. Location of SMAD4 mutations identified in Myhre syndrome.


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Further Reading

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Michot, Caroline, Le Goff, Carine, and Cormier‐Daire, Valérie(Nov 2016) Molecular Genetics of Myhre Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026841]