SMAD4 – Myhre syndrome

Myhre syndrome is a rare autosomal dominant connective tissue disorder characterized by short stature, distinctive facial dysmorphism, muscular pseudohypertrophy, stiff skin, joint limitation, and hearing loss (MONDO:0007688). Pathogenic gain-of-function missense variants in SMAD4 (HGNC:6770) have been established as the molecular cause, disrupting TGF-β/BMP signaling and driving a progressive fibroproliferative phenotype.

Clinical Validity

A Definitive SMAD4–Myhre syndrome association is supported by >60 molecularly confirmed cases over >10 years, including multigenerational transmission and functional concordance. The narrow mutation spectrum (hot-spot at residues Ile500 and Arg496) with consistent phenotypic overlap underpins this categorization.

Genetic Evidence

Inheritance is autosomal dominant. Recurrent heterozygous missense variants affecting codon 500 (p.Ile500Thr/Met/Val) and codon 496 (p.Arg496Cys/His) have been reported in >60 unrelated probands ([PMID:22158539]) and catalogued in case series ([PMID:24424121]). Familial segregation with transmission from an affected parent to multiple offspring (three affected relatives) has been documented for the recurrent c.1486C>T (p.Arg496Cys) variant ([PMID:31595668]).

Functional Evidence

Patient fibroblasts harboring Myhre-associated SMAD4 variants display increased SMAD4 protein levels, impaired extracellular matrix deposition, and dysregulated metalloproteinase expression; these defects were normalized by losartan treatment ([PMID:24398790]). Dual-luciferase assays of p.Ile500Val/Thr/Cys variants demonstrated gain-of-function with increased transcriptional activity at SMAD-binding elements ([PMID:31654632]). Biochemical studies reveal that SMAD4-Ile500Val acts in a dominant-negative manner, forming stable heterotrimers that perturb TGF-β and BMP signaling ([PMID:36194927]).

Mechanism of Pathogenicity

Myhre syndrome SMAD4 variants cluster in the MH2 domain, impair monoubiquitination, and lead to aberrant nuclear accumulation and transcriptional activation. The resulting gain-of-function promotes tissue fibrosis and multisystem complications, including life-threatening cardiovascular and airway involvement.

Integration & Clinical Utility

The tight allelic spectrum, consistent segregation, and robust functional concordance establish SMAD4 as the definitive gene for Myhre syndrome. Molecular confirmation guides clinical management—prompting surveillance for pericarditis, laryngotracheal stenosis, hormonal dysfunction, and fibrotic complications—and informs genetic counseling and family planning.

Key Take-home: SMAD4 gain-of-function missense variants cause Myhre syndrome via dominant-negative dysregulation of TGF-β/BMP signaling, warranting early genetic testing in patients with characteristic fibroproliferative and multisystem features.

References

• Nature Genetics • 2011 • Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome PMID:22158539
• American Journal of Medical Genetics Part A • 2019 • Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum PMID:31595668
• European Journal of Human Genetics • 2014 • SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan PMID:24398790
• Clinica Chimica Acta • 2020 • The first two Chinese Myhre syndrome patients with the recurrent SMAD4 pathogenic variants: Functional consequences and clinical diversity PMID:31654632
• Differentiation • 2022 • Myhre syndrome is caused by dominant-negative dysregulation of SMAD4 and other co-factors PMID:36194927
• American Journal of Human Genetics • 2012 • A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome PMID:22243968
• European Journal of Human Genetics • 2014 • Myhre and LAPS syndromes: clinical and molecular review of 32 patients PMID:24424121

Evidence Based Scoring (AI generated)