Le Goff C, Michot C, Cormier-Daire V
Département de Génétique, Unité INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades, Paris, France.
Clin Genet. 2014 Jun;85(6):503-13. doi: 10.1111/cge.12365. Epub 2014 Apr 2.
Myhre syndrome (MS) is a developmental disorder characterized by typical facial dysmorphism, thickened skin, joint limitation and muscular pseudohypertrophy. Other features include brachydactyly, short stature, intellectual deficiency with behavioral problems and deafness. We identified SMAD4 as the gene responsible for MS. The identification of SMAD4 mutations in Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature (LAPS) cases supports that LAPS and MS are a unique entity. The long-term follow up of patients shows that these conditions are progressive with life threatening complications. All mutations are de novo and changing in the majority of cases Ile500, located in the MH2 domain involved in transcriptional activation. We further showed an impairment of the transcriptional regulation via TGFβ target genes in patient fibroblasts. Finally, the absence of SMAD4 mutations in three MS cases may support genetic heterogeneity.
迈尔综合征（MS）是一种发育障碍性疾病，其特征为典型的面部畸形、皮肤增厚、关节受限和肌肉假性肥大。其他特征包括短指畸形、身材矮小、伴有行为问题的智力缺陷和耳聋。我们确定SMAD4是导致MS的基因。在喉气管狭窄、关节病、凸颌和身材矮小（LAPS）病例中发现SMAD4突变，这支持LAPS和MS是一种独特的疾病实体。对患者的长期随访表明，这些病症会逐渐发展并伴有危及生命的并发症。所有突变都是新发的，并且在大多数病例中位于参与转录激活的MH2结构域的Ile500发生改变。我们进一步表明，患者成纤维细胞中通过TGFβ靶基因的转录调控受损。最后，三例MS病例中未检测到SMAD4突变可能支持遗传异质性。
