Implications of Splicing Alterations in the Onset and Phenotypic Variability of a Family with Subclinical Manifestation of Peutz–Jeghers Syndrome: Bioinformatic and Molecular Evidence
| Autor: | Massimo Martinelli, Francesca Cammarota, Andrea Cerasuolo, Erasmo Miele, Francesca Duraturo, Annamaria Staiano, Paola Izzo, Marina De Rosa |
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| Přispěvatelé: | Cerasuolo, A., Cammarota, F., Duraturo, F., Staiano, A., Martinelli, M., Miele, E., Izzo, P., De Rosa, M. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Peutz-Jeghers Syndrome Presymptomatic diagnosi Café au lait spot medicine.disease_cause lcsh:Chemistry Fathers Exon café au lait spots 0302 clinical medicine AMP-Activated Protein Kinase Kinases Peutz–Jeghers Syndrome (PJS) Child lcsh:QH301-705.5 Spectroscopy Genetics Mutation cancer prevention Cafe-au-Lait Spots Exons General Medicine Pedigree Computer Science Applications Enhancer Elements Genetic Phenotype presymptomatic diagnosis 030220 oncology & carcinogenesis RNA splicing Female Silent mutation Enhancer Splicing Element Mothers Protein Serine-Threonine Kinases Biology Polymorphism Single Nucleotide risk management Article Catalysis Inorganic Chemistry 03 medical and health sciences Germline mutation medicine Humans Genetic Testing Physical and Theoretical Chemistry Allele Molecular Biology Gene Alleles Germ-Line Mutation Family Health Sequence Analysis RNA Organic Chemistry Wild type Computational Biology splicing variants Alternative Splicing 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Gene Expression Regulation |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 21 International Journal of Molecular Sciences, Vol 21, Iss 8201, p 8201 (2020) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms21218201 |
| Popis: | Peutz&ndash Jeghers Syndrome (PJS) is an autosomal dominant pre-cancerous disorder caused in 80&ndash 90% of cases by germline mutations in the tumor suppressor gene STK11. We performed a genetic test of the STK11 gene in two Italian young sisters suspected of PJS, since they showed pathognomonic café au lait spots in absence of other symptoms and familiarity. Sequencing of all exons of STK11 gene and other 8 genes, suggested to be involved in hamartomatous syndromes, (PTEN, BMPR1A, SDHB, SDHD, SMAD4, AKT1, ENG, PIK3CA) led to the identification in both the probands of a novel germline silent mutation named c.597 G> A, hitting the last nucleotide of exon 4. Interestingly, genetic testing of the two probands&rsquo parents showed that their unaffected father was carrier of this mutation. Moreover, he carried a second intronic substitution named c.465-51 T> C (rs2075606) which was not inherited by his daughters. We also observed that all the family members carrying the c.597 G> A mutation presented an aberrant splice variant of STK11 mRNA lacking exon 4. Furthermore, in silico analysis of c.465-51 T> C substitution showed that it may activate an Enhancer Splicing Element. Finally, qRT-PCR analysis of STK11 expression levels showed a slight downregulation of the wild type allele in the father and a 2-fold downregulation in the probands compared to the unaffected mother. Our results have led the hypothesis that the c.465-51 T> C intronic variant, which segregates with the wild type allele, could increase the splicing effectiveness of STK11 wild-type allele and compensate the side effect of the c.597 G> A splicing mutation, being responsible for the phenotypic variability observed within this family. This finding highlight the importance of RNA analysis in genetic testing, remarking that silent DNA variant can often be splicing variant involved in disease onset and progression. The identification of these variants has a crucial role to ensure an appropriate follow-up and cancer prevention in at-risk individuals. |
| Databáze: | OpenAIRE |
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