RGD Reference Report - Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

Authors: Gallione, C  Aylsworth, AS  Beis, J  Berk, T  Bernhardt, B  Clark, RD  Clericuzio, C  Danesino, C  Drautz, J  Fahl, J  Fan, Z  Faughnan, ME  Ganguly, A  Garvie, J  Henderson, K  Kini, U  Leedom, T  Ludman, M  Lux, A  Maisenbacher, M  Mazzucco, S  Olivieri, C  Ploos van Amstel, JK  Prigoda-Lee, N  Pyeritz, RE  Reardon, W  Vandezande, K  Waldman, JD  White RI, JR  Williams, CA  Marchuk, DA 
Citation: Gallione C, etal., Am J Med Genet A. 2010 Feb;152A(2):333-9. doi: 10.1002/ajmg.a.33206.
RGD ID: 11062720
Pubmed: PMID:20101697   (View Abstract at PubMed)
DOI: DOI:10.1002/ajmg.a.33206   (Journal Full-text)

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SMAD4Humanjuvenile polyposis-hereditary hemorrhagic telangiectasia syndrome  IAGP DNA:mutations:exon:multipleRGD 
Smad4Ratjuvenile polyposis-hereditary hemorrhagic telangiectasia syndrome  ISOSMAD4 (Homo sapiens)DNA:mutations:exon:multipleRGD 
Smad4Mousejuvenile polyposis-hereditary hemorrhagic telangiectasia syndrome  ISOSMAD4 (Homo sapiens)DNA:mutations:exon:multipleRGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SMAD4HumanEpistaxis  IAGP DNA:mutations:exon:multipleRGD 
Objects Annotated

Genes (Rattus norvegicus)
Smad4  (SMAD family member 4)

Genes (Mus musculus)
Smad4  (SMAD family member 4)

Genes (Homo sapiens)
SMAD4  (SMAD family member 4)


Additional Information