Myhre syndrome is caused by dominant-negative dysregulation of SMAD4 and other co-factors

Alankarage, Dimuthu; Enriquez, Annabelle; Steiner, Robert D.; Raggio, Cathy L.; Higgins, Megan; Milnes, Di; Humphreys, David T.; Duncan, Emma L.; Sparrow, Duncan B.; Giampietro, Philip F.; Chapman, Gavin; Dunwoodie, Sally L.

doi:10.1016/j.diff.2022.09.002

Cited by 5 publications

(1 citation statement)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concerning skeletal dysplasia, total protein extract from fibroblasts of patients with MS showed increased SMAD4 expression due to impaired protein ubiquitination by E3 ligases, increased SMAD2/3 phosphorylation, and aberrant expression of TGF-β and BMP target genes, suggesting a GOF effect (77). A recent study on the effect of the p.Ile500Val change in transfected HEK293T cells also showed a dysregulated expression of TGF-β and BMP target genes (5). However, these results indicated a dominant-negative effect of the p.Ile500Val mutation on R-SMADs rather than a GOF effect.…”

Section: Myhre Syndromementioning

confidence: 98%

TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature

Costantini,

Guasto,

Cormier-Daire

2023

Annu. Rev. Genom. Hum. Genet.

View full text Add to dashboard Cite

The transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways play a pivotal role in bone development and skeletal health. More than 30 different types of skeletal dysplasia are now known to be caused by pathogenic variants in genes that belong to the TGF-β superfamily and/or regulate TGF-β/BMP bioavailability. This review describes the latest advances in skeletal dysplasia that is due to impaired TGF-β/BMP signaling and results in short stature (acromelic dysplasia and cardiospondylocarpofacial syndrome) or tall stature (Marfan syndrome). We thoroughly describe the clinical features of the patients, the underlying genetic findings, and the pathomolecular mechanisms leading to disease, which have been investigated mainly using patient-derived skin fibroblasts and mouse models. Although no pharmacological treatment is yet available for skeletal dysplasia due to impaired TGF-β/BMP signaling, in recent years advances in the use of drugs targeting TGF-β have been made, and we also discuss these advances.

show abstract

Section: Myhre Syndromementioning

confidence: 98%

TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature

Costantini,

Guasto,

Cormier-Daire

2023

Annu. Rev. Genom. Hum. Genet.

View full text Add to dashboard Cite

show abstract

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016–2023)

Lin,

Scimone,

Thom

et al. 2024

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016–2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence‐based guidelines in anticipation of disease‐specific therapies.

show abstract

SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline

Wood,

Tong,

Motta

et al. 2024

The American Journal of Human Genetics

View full text Add to dashboard Cite

Myhre syndrome is caused by dominant-negative dysregulation of SMAD4 and other co-factors

Cited by 5 publications

References 53 publications

TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature

TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016–2023)

SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline

Contact Info

Product

Resources

About