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

Abstract

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.

Genetic alterations in Japanese extrahepatic biliary tract cancer

“…Mutations at codons 352 and 532 are relatively infrequent (43); a total of 10 cases of a mutation at codon 352 and three cases at codon 532 are present in the COSMIC database. Although p.G352E is one of the ten cases, it was identified as a pathological mutation as the germ line p.G352E mutation has been reported in patients with juvenile polyposis and hereditary hemorrhagic telangiectasia (44). Although Ala532 is located outside of mutation cluster region (MCR) between codons 330 and 370, it is within the three-helix bundle (codon 445-540), which is reported to be functionally important (45).…”

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…127 There were previous reports that SMAD4 mutations in HHT tended to cluster in part of the gene encoding the MH2 domain, but a recent more extensive study has shown HHTcausing mutations also occur in other parts of SMAD4. 127 As would be expected for a disease gene frequency of 1 in 5,000, there are occasional families in which two proven HHT mutations co-segregate. 122 Individual series describe ENG or ACVRL1 predominance.…”

“…The majority of HHT patients will have HHT1 due to mutations in ENG encoding endoglin, 19 or HHT2 due to mutations in ACVRL1 encoding activin receptor-like kinase (ALK1). 20 One to two percent of cases 127 have mutations in SMAD4, mutations that also cause the gastrointestinal epithelial precancerous state of juvenile polyposis. 11 There are at least two further unidentified genes that can cause pure HHT, HHT3 between 141.9-146.4Mb on chromosome 5q, 128,129 and HHT4 on chromosome 7p between D7S2252 and D7S510.…”

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

“…For these eight genes, it is either gain-of-function or dominant negative, thereby showing statistical enrichment for NHI mechanisms (p ¼ 2.66E-03, Fisher's exact test; Table S14 and S15). For two of the three remaining genes (GRIN2B [MIM 138252] and SMAD4 [MIM 600993]) both HI and NHI consequences have been reported, [36][37][38][39] suggesting that for mutations in these genes more complex genotype-phenotype relations might exist, where HI and NHI mechanisms cause clinically distinct ID/DD-related disorders. For KCNQ2 (MIM 602235), the reported mutational mechanism is HI although a literature search also revealed cases with dominant-negative effects.…”