Redefining the PTEN Promoter: Identification of Two Upstream Transcription Start Regions

Germline mutation of PTEN is causally observed in Cowden syndrome (CS) and is one of the most common genetic causes of autism spectrum disorder (ASD). However, the majority of individuals who present with CS-like clinical features are found to be PTEN-mutation negative. Reassessment of PTEN promoter regulation may help explain abnormal PTEN dosage, as only the minimal promoter and coding regions are currently included in diagnostic PTEN mutation analysis. We reanalyzed the architecture of the PTEN promoter using next-generation sequencing datasets. Specifically, run-on sequencing assays identified two additional TSRs at -2052 and -1907 basepairs from the start of PTEN, thus redefining the PTEN promoter and extending the PTEN 5-UTR. The upstream TSRs described are active in cancer cell lines and human cancer and normal tissue. Further, these TSRs can produce novel PTEN transcripts due to the introduction of new splice sites. Evaluation of transcription factor binding specific to the upstream TSRs shows overrepresentation of TFs involved in inflammatory processes. Together, these data suggest that potentially clinically relevant promoter variants upstream of the known promoter may be overlooked in indivduals considered PTEN germline mutation-negative and may also explain lack of PTEN expression in sporadic neoplasias without PTEN somatic structural defects.

Download Full-text

Influence of Next-Generation Sequencing on Advancements in the Diagnosis of Major Psychiatric Diseases - A Review

Pakistan Journal of Medicine and Dentistry ◽

10.36283/pjmd9-2/022 ◽

2020 ◽

Author(s):

Maheen Nisar

Keyword(s):

Next Generation Sequencing ◽

Mental Disorders ◽

Attention Deficit Disorder ◽

Autism Spectrum ◽

Next Generation ◽

Single Nucleotide Variants ◽

New Genes ◽

Depth Analysis ◽

Pubmed Search ◽

Generation Sequencing

Rapid progress is being made in the development of next-generation sequencing (NGS) technologies, allowing repeated findings of new genes and a more in-depth analysis of genetic polymorphisms behind the pathogenesis of a disease. In a field such as psychiatry, characteristic of vague and highly variable somatic manifestations, these technologies have brought great advances towards diagnosing various psychiatric and mental disorders, identifying high-risk individuals and towards more effective corresponding treatment. Psychiatry has the difficult task of diagnosing and treating mental disorders without being able to invariably and definitively establish the properties of its illness. This calls for diagnostic technologies that go beyond the traditional ways of gene manipulation to more advanced methods mainly focusing on new gene polymorphism discoveries, one of them being NGS. This enables the identification of hundreds of common and rare genetic variations contributing to behavioral and psychological conditions. Clinical NGS has been useful to detect copy number and single nucleotide variants and to identify structural rearrangements that have been challenging for standard bioinformatics algorithms. The main objective of this article is to review the recent applications of NGS in the diagnosis of major psychiatric disorders, and hence gauge the extent of its impact in the field. A comprehensive PubMed search was conducted and papers published from 2013-2018 were included, using the keywords, “schizophrenia” or “bipolar disorder” or “depressive disorder” or “attention deficit disorder” or “autism spectrum disorder” and “next-generation sequencing”

Download Full-text

Bariatric Surgery for Cowden Syndrome with PTEN Mutation: a Case Report

Obesity Surgery ◽

10.1007/s11695-021-05231-1 ◽

2021 ◽

Author(s):

Han Na Jang ◽

Sa Hong Kim ◽

Young Min Cho ◽

Do Joong Park

Keyword(s):

Bariatric Surgery ◽

Case Report ◽

Cowden Syndrome ◽

Pten Mutation

Download Full-text

PTEN mutation in a family with Cowden syndrome and autism

American Journal of Medical Genetics ◽

10.1002/ajmg.1477 ◽

2001 ◽

Vol 105 (6) ◽

pp. 521-524 ◽

Cited By ~ 137

Author(s):

Aleide Goffin ◽

Lies H. Hoefsloot ◽

Ermanno Bosgoed ◽

Ann Swillen ◽

Jean-Pierre Fryns

Keyword(s):

Cowden Syndrome ◽

Pten Mutation

Download Full-text

Multiple Primary Tumors in a Family with Li-Fraumeni Syndrome with a TP53 Germline Mutation Identified by Next-Generation Sequencing

The International Journal of Biological Markers ◽

10.5301/jbm.5000227 ◽

2016 ◽

Vol 31 (4) ◽

pp. 461-465 ◽

Cited By ~ 2

Author(s):

Valentina Zampiga ◽

Rita Danesi ◽

Gianluca Tedaldi ◽

Michela Tebaldi ◽

Ilaria Cangini ◽

...

Keyword(s):

Next Generation Sequencing ◽

Genetic Analysis ◽

Germline Mutation ◽

Tp53 Mutation ◽

Primary Tumors ◽

Li Fraumeni Syndrome ◽

Multiple Primary Tumors ◽

Targeted Ngs ◽

Multiple Primary ◽

Generation Sequencing

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder occurring at a young age that predisposes individuals to multiple forms of cancer and to a heterogeneous spectrum of malignancies. We describe the clinical history of a patient who had 5 primary malignant cancers and a familiar history consistent with LFS. We analyzed the genomic DNA of the proband and her relatives by next-generation sequencing (NGS) technology using an enrichment protocol for the simultaneous sequencing of 94 genes involved in hereditary cancers. Genetic analysis of the proband revealed a TP53 germline mutation in exon 5 determining a nucleotide alteration at codon 175 (R175H), a hot spot mutation site related to LFS and a reported pathogenic mutation. The proband daughter's and brother's DNA did not carry the TP53 mutation but they had some rare variants in common with the proband, in addition to other variants with a still unclear role. In conclusion, we identified a TP53 mutation in a patient with multiple primary tumors and a family history characterized by a severe susceptibility to cancer. The genetic analysis by targeted NGS led to the identification of the genetic background and to the exclusion of a cancer risk for the family members. Targeted NGS represents an efficient approach for the identification of mutations in families with a heterogeneous phenotype.

Download Full-text

Activation of sphingosine 1-phosphate receptor 2 attenuates chemotherapy-induced neuropathy

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011699 ◽

2019 ◽

Vol 295 (4) ◽

pp. 1143-1152 ◽

Cited By ~ 9

Author(s):

Wei Wang ◽

Ping Xiang ◽

Wee Siong Chew ◽

Federico Torta ◽

Aishwarya Bandla ◽

...

Keyword(s):

Dorsal Root ◽

Disease Modeling ◽

Human Cancer ◽

Human Study ◽

Oxaliplatin Treatment ◽

Promising Therapeutic Approach ◽

Pharmacodynamic Analysis ◽

Sphingosine 1 Phosphate ◽

Inflammatory Processes ◽

Study Participants

Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1–5. In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2. We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.

Download Full-text