Novel SMAD4 mutation causing Myhre syndrome

Am J Med Genet A. 2014 Jul;164A(7):1835-40. doi: 10.1002/ajmg.a.36544. Epub 2014 Apr 8.


Myhre syndrome (MYHRS, OMIM 139210) is an autosomal dominant disorder characterized by developmental and growth delay, athletic muscular built, variable cognitive deficits, skeletal anomalies, stiffness of joints, distinctive facial gestalt and deafness. Recently, SMAD4 (OMIM 600993) was identified by exome sequencing as the disease gene mutated in MYHRS. Previously only three missense mutations affecting Ile500 (p.Ile500Thr, p.Ile500Val, and p.Ile500Met) have been described in 22 unrelated subjects with MYHRS or a clinically related phenotype. Here we report on a 15-year-old boy with typical MYHRS and a novel heterozygous SMAD4 missense mutation affecting residue Arg496. This finding provides further information about the distinctive SMAD4 mutation spectrum in MYHRS. In silico structural analyses exploring the impact of the Arg-to-Cys change at codon 496 suggested that conformational changes promoted by replacement of Arg496 impact the stability of the SMAD heterotrimer and/or proper SMAD4 ubiquitination.

Keywords: Myhre syndrome; SMAD4; TGF-β pathway; mutation analysis; structural analyses.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • Codon
  • Cryptorchidism / diagnosis*
  • Cryptorchidism / genetics*
  • Facies
  • Genetic Association Studies*
  • Growth Disorders / diagnosis*
  • Growth Disorders / genetics*
  • Hand Deformities, Congenital / diagnosis*
  • Hand Deformities, Congenital / genetics*
  • Humans
  • Hypertrophy / diagnosis*
  • Hypertrophy / genetics*
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics*
  • Joint Diseases / diagnosis*
  • Joint Diseases / genetics*
  • Male
  • Models, Molecular
  • Mutation*
  • Phenotype
  • Protein Conformation
  • Protein Multimerization
  • Protein Stability
  • Sequence Analysis, DNA
  • Smad4 Protein / chemistry
  • Smad4 Protein / genetics*


  • Codon
  • Smad4 Protein

Supplementary concepts

  • Growth mental deficiency syndrome of Myhre

Associated data

  • OMIM/OMIM139210
  • OMIM/OMIM600993