Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome.
Hannah Jinlian ChenTodd RomighKaitlin SesockCharis EngPublished in: Human mutation (2017)
Germline mutations in the tumor-suppressor gene PTEN predispose to subsets of Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and autism. Evidence-based classification of PTEN variants as either deleterious or benign is urgently needed for accurate molecular diagnosis and gene-informed genetic counseling. We studied 34 different germline PTEN intronic variants from 61 CS patients, characterized their PTEN mRNA processing, and analyzed PTEN expression and downstream readouts of P-AKT and P-ERK1/2. While we found that many mutations near splice junctions result in exon skipping, we also identified the presence of cryptic splicing that resulted in premature termination or a shift in isoform usage. PTEN protein expression is significantly lower in the group with splicing changes while P-AKT, but not P-ERK1/2, is significantly increased. Our observations of these PTEN intronic variants should contribute to the determination of pathogenicity of PTEN intronic variants and aid in genetic counseling.
Keyphrases
- cell proliferation
- pi k akt
- copy number
- signaling pathway
- genome wide
- case report
- autism spectrum disorder
- dna repair
- poor prognosis
- gene expression
- machine learning
- high resolution
- ejection fraction
- cystic fibrosis
- escherichia coli
- transcription factor
- single molecule
- chronic kidney disease
- human immunodeficiency virus
- binding protein