Myhre syndrome.

Area of Science:

• Genetics
• Developmental Biology
• Molecular Medicine

Background:

• Myhre syndrome (MS) is a rare developmental disorder with distinct facial features, skin and joint abnormalities, and intellectual deficits.
• Previous research has not conclusively identified the genetic basis for Myhre syndrome.
• Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature (LAPS) shares overlapping features with MS, suggesting a potential common etiology.

Purpose of the Study:

• To identify the gene responsible for Myhre syndrome.
• To investigate the molecular mechanisms underlying MS pathogenesis.
• To determine the relationship between MS and LAPS.

Main Methods:

• Whole-exome sequencing was performed on patients with Myhre syndrome.
• Sanger sequencing was used to confirm identified mutations.
• Functional studies involving patient-derived fibroblasts were conducted to assess SMAD4 protein function and TGFβ signaling pathways.

Main Results:

• SMAD4 was identified as the gene causally linked to Myhre syndrome.
• Mutations in SMAD4 were also found in patients with LAPS, supporting MS and LAPS as a single entity.
• Patient fibroblasts exhibited impaired transcriptional regulation of TGFβ target genes, indicating a functional consequence of SMAD4 mutations.
• All identified mutations were de novo, with a common alteration at Ile500 in the MH2 domain.

Conclusions:

• SMAD4 mutations are the primary cause of Myhre syndrome and LAPS.
• The identified mutations disrupt SMAD4's role in transcriptional activation, leading to developmental abnormalities.
• While SMAD4 mutations explain most MS cases, genetic heterogeneity may exist in a subset of patients.
• MS and LAPS are progressive disorders with potentially life-threatening complications, underscoring the need for long-term patient management.