S100PBP (S100P binding protein)

Review on S100PBP (S100P binding protein), with data on DNA, on the protein encoded, and where the gene is implicated

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1

Modeling complex ecological economic systems: toward an evolutionary, dynamic understanding of people and nature

Recent understanding about system dynamics and predictability that has emerged from the study of complex systems is creating new tools for modeling interactions between anthropogenic and natural systems. A range of techniques has become available through advances in computer speed and accessibility and by implementing a broad, interdisciplinary systems view

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing

Epigenetic dysregulation in pituitary tumors

Pituitary tumors are common intracranial neoplasms associated with significant morbidity due to hormonal dysregulation and neurologic symptoms. Somatic mutations are uncommon in sporadic pituitary adenomas, and only few monogenic conditions are associated with pituitary tumors. However, increasing evidence suggests that aberrant epigenetic modifications are found in pituitary tumors. In this review, we describe these mechanisms, including DNA methylation, histone modification and microRNA expression, and the evidence supporting their dysregulation in pituitary tumors, as well as their regulation of pro-tumorigenic genes. In addition, we provide an overview of findings from preclinical studies investigating the use of histone deacetylase inhibitors to treat pituitary adenomas and the need for further studies involving epigenetic drugs and functional characterization of epigenetic dysregulation. </jats:p

Molecular Genetic Studies of Pancreatic Neuroendocrine Tumors: New Therapeutic Approaches

Pancreatic neuroendocrine tumors (PNETs) can occur as sporadic neoplasms or as part of hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1). MEN1, which is an autosomal dominant disorder, is due to loss-of-function mutations of the tumor suppressor MEN1 gene that encodes menin. Approximately 40% of nonfamilial (ie, sporadic) PNETs have MEN1 mutations, with subsequent loss of menin, which acts as a tumor suppressor. Menin is a scaffold protein with roles in transcriptional regulation, genome stability, DNA repair, protein degradation, cell motility and adhesion, microRNA biogenesis, cell division, cell cycle control, epigenetic regulation, and Wnt signaling. Emerging therapies targeting the functional roles of menin with Men1 gene replacement therapy, epigenetic modulators, and antagonists of Wnt-signaling may prove useful for future treatment of PNETs

Preclinical drug studies in MEN1-related neuroendocrine neoplasms (MEN1-NENs)

Neuroendocrine neoplasms (NENs) occur usually as sporadic tumours; however, rarely, they may arise in the context of a hereditary syndrome, such as multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterised by the combined development of pancreatic NENs (pNENs) together with parathyroid and anterior pituitary tumours. The therapeutic decision for sporadic pNENs patients is multi-disciplinary and complex: based on the grade and stage of the tumor, various options (and their combinations) are considered, such as surgical excision (either curative or for debulking aims), biological drugs (somatostatin analogues), targeted therapies (mTOR inhibitors or tyrosine kinases (TK)/receptors inhibitors), peptide receptor radioligand therapy (PRRT), chemotherapy, and liver-directed therapies. However, treatment of MEN1-related NENs’ patients is even more challenging, as these tumours are usually multifocal with co-existing foci of heterogeneous biology and malignant potential, rendering them more resistant to the conventional therapies used in their sporadic counterparts, and therefore associated with a poorer prognosis. Moreover, clinical data using standard therapeutic options in MEN1-related NENs are scarce. Recent preclinical studies have identified potentially new targeted therapeutic options for treating MEN1-associated NENs, such as epigenetic modulators, Wnt pathway-targeting β-catenin antagonists, Ras signalling modulators, Akt/mTOR signalling modulators, novel somatostatin receptors analogues, anti-angiogenic drugs, as well as MEN1 gene replacement therapy. The present review aims to summarize these novel therapeutic opportunities for NENs developing in the context of MEN1 syndrome, with an emphasis on pancreatic NENs, as they are the most frequent ones studied in MEN1-NENs models to date; moreover, due to the recent shifting nomenclature of ‘pituitary adenomas’ to ‘pituitary neuroendocrine neoplasms’, relevant data on MEN1-pituitary tumours, when appropriate, are briefly described