A Restricted Spectrum of Mutations in the SMAD4 Tumor-Suppressor Gene Underlies Myhre Syndrome

Abstract

Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.

Chondrodysplasias and TGFβ signaling

“…The mutations were not observed in MS parents, confirming that they occurred de novo. 44 Caputo et al 45 confirmed these results by reporting eight other MS cases with SMAD4 mutations also altering the Ile500 residue.…”

Myhre and LAPS syndromes: clinical and molecular review of 32 patients

“…17 All SMAD4 mutations identified occured de novo and no familial transmission has been reported so far. The high average paternal age at birth (436 years), combined with the prevalence of Ile500 change due to mainly two nucleotides changes in SMAD4, may suggest a mechanism of protein-driven selfish selection in sperm.…”

“…Recently, Le Goff et al 16 identified missense SMAD4 heterozygous mutations, affecting the conserved Ile500 residue as a cause of Myhre syndrome. Shortly after, Caputo et al 17 reported eight other Myhre syndrome cases with SMAD4 mutations altering the Ile500 residue in all their patients. The same mutation was also identified in two patients with LAPS syndrome 18 supporting the concept that Myhre and LAPS syndromes are phenotypic variants of a single entity.…”

Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

“…As described below, this subset requires additional screening for these vascular complications. Interestingly, a restricted spectrum of SMAD4 mutations cause Myhre syndrome, defined by developmental and short stature, athletic build, skeletal anomalies, joints stiffness, distinct facial features, and deafness (62).…”