This variant is classified as a variant of unknown significance because its contribution to hamartomatous polyposis and gastrointestinal ganglioneuromas (see 158350) has not been confirmed.
In a 38-year-old Caucasian man with hamartomatous polyposis syndrome (HPS), who was negative for mutation in known HPS-associated genes, Ngeow et al. (2015) performed whole-exome sequencing and identified a heterozygous germline val90-to-met (V90M) substitution. Functional analysis in transfected HEK293 cells showed lower PTEN (601728) mRNA and protein levels in patient lymphoblastoid cell lines compared to healthy controls, and reduced PTEN protein expression was also observed in polyp tissue from the patient. However, because SMAD9 was unable to directly bind the PTEN promoter, Ngeow et al. (2015) studied miR21 (611020), a direct downstream effector of the BMP-SMAD9 signaling pathway known to target PTEN directly and suppress PTEN expression. The authors demonstrated that miR21 expression increased significantly in BMP4 (112262)-treated mutant cells compared to wildtype, due to increased binding of mutant SMAD9 to primary miR21 (pri-miR21) and consequent increased processing of pri-miR21 into mature miR21. Ngeow et al. (2015) concluded that V90M is a gain-of-function mutation resulting in increased miR21 expression, which causes decreased PTEN mRNA and protein stability. The proband presented with persistent diarrhea and weight loss, and colonoscopy revealed diffuse 3- to 5-mm polyps throughout his colon. Histologic analysis showed that these were hamartomatous polyps admixed with either mature adipose or ganglioneuromatous proliferation. The proband had an affected brother who was diagnosed with polyposis in his 20s; their father had diffuse polyposis and died in his 40s, and a paternal aunt and uncle died from early-onset colorectal cancer in their 40s. DNA was unavailable from affected family members.
