scholarly journals Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review

2019 ◽  
Vol 104 (12) ◽  
pp. 6229-6237 ◽  
Author(s):  
Chiho Sugisawa ◽  
Tetsuya Takamizawa ◽  
Kiyomi Abe ◽  
Tomonobu Hasegawa ◽  
Kentaro Shiga ◽  
...  
Keyword(s):  
Literature Review ◽  
Single Gene ◽  
Mutation Screening ◽  
Gene Mutations ◽  
Serum Prolactin ◽  
Loss Of Function ◽  
Mutation Carriers ◽  
Tsh Levels ◽  
Tsh Deficiency

Abstract Context Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. Objectives To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. Patients and Methods Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. Results Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. Conclusions The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.

A Novel Loss of Function Melanocortin-4-Receptor Mutation (MC4R-F313Sfs*29) in Morbid Obesity

2020 ◽  
Author(s):  
Elisabetta Trevellin ◽  
Marnie Granzotto ◽  
Cristina Host ◽  
Francesca Grisan ◽  
Diego De Stefani ◽  
...  
Keyword(s):  
Early Onset ◽  
Functional Characterization ◽  
Gene Mutations ◽  
Melanocortin Receptor ◽  
Hek293 Cells ◽  
Intracellular Camp ◽  
Loss Of Function ◽  
Mc4r Gene ◽  
Melanocortin 4 Receptor

Abstract Context Melanocortin receptor-4 (MC4R) gene mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. Objective To explore whether and how a novel heterozygous MC4R variant (MC4R-F313Sfs*29), identified in a young boy (body mass index [BMI] 38.8 kg/m2) during a mutation analysis conducted in a cohort of patients with obesity, plays a determinant pathophysiological role in the obesity development. Design Setting and Patients The genetic screening was carried out in a total of 209 unrelated patients with obesity (BMI ≥ 35 kg/m2). Structural and functional characterization of the F313Sfs*29-mutated MC4R was performed using computational approaches and in vitro, using HEK293 cells transfected with genetically encoded biosensors for cAMP and Ca2+. Results The F313Sfs*29 was the only variant identified. In vitro experiments showed that HEK293 cells transfected with the mutated form of MC4R did not increase intracellular cAMP or Ca2+ levels after stimulation with a specific agonist in comparison with HEK293 cells transfected with the wild type form of MC4R (∆R/R0 = -90% ± 8%; P < 0.001). In silico modeling showed that the F313Sfs*29 mutation causes a major reorganization in the cytosolic domain of MC4R, thus reducing the affinity of the putative GalphaS binding site. Conclusions The newly discovered F313Sfs*29 variant of MC4R may be involved in the impairment of α-MSH-induced cAMP and Ca2+ signaling, blunting intracellular G protein-mediated signal transduction. This alteration might have led to the dysregulation of satiety signaling, resulting in hyperphagia and early onset of obesity.

scholarly journals Diversity of ARSACS Mutations in French-Canadians

2013 ◽  
Vol 40 (1) ◽  
pp. 61-66 ◽  
Author(s):  
I. Thiffault ◽  
M.J. Dicaire ◽  
M. Tetreault ◽  
K.N. Huang ◽  
J. Demers-Lamarche ◽  
...  
Keyword(s):  
Low Cost ◽  
Phenotypic Variability ◽  
Mutation Screening ◽  
Gene Mutations ◽  
Genotypic Diversity ◽  
Loss Of Function ◽  
French Canadian ◽  
Spastic Ataxia ◽  
Large Gene ◽  
Canadian Population

Abstract:Background:The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two knownSACSmutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability.Methods:Search forSACSmutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin.Results:A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98SACSmutations did not uncover carriers of two mutations. Compounds heterozygotes for one missenseSACSmutation were found to minimally express sacsin.Conclusions:The large number ofSACSmutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge ofSACSmutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

scholarly journals Do alterations in gene expressions influence tumorigenesis in the transmissible venereal tumor in dogs?

2020 ◽  
Vol 50 (11) ◽  
Author(s):  
Haline Ballestero Fêo ◽  
Luis Mauricio Montoya Flórez ◽  
Ricardo Seiti Yamatogi ◽  
Anderson do Prado Duzanski ◽  
João Pessoa Araújo Junior ◽  
...  
Keyword(s):  
Cell Culture ◽  
Tumor Suppressor Genes ◽  
Primary Cell Culture ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Primary Cell ◽  
Loss Of Function ◽  
Gene Expressions

ABSTRACT: Canine transmissible venereal tumor (CTVT) is a transmissible neoplasm, which spreads naturally between dogs through the halogenic transfer of tumor cells, mainly during coitus. It is the oldest known tumoral lineage in nature and reports on gene mutations have been extended. Also, this tumor shares several genetic mutations with some cancers in humans, among them lung carcinomas, melanoma, prostate, breast, among other cancers. Thus, expression of tumor suppressor genes such as TP53, P21, and apoptosis-related genes such as BAX, BCL-2, and BCL-xL, both in vivo and in vitro (primary cell culture) were quantified. In the present study, the comparison of gene expression, the TP53 gene, in most cases, was shown to be high in the majority of tissues (65%) and primary cell culture (100%), while BCL-2, BCL-xL, and BAX presented variation among the animals analyzed. Moreover, in these situations, the results suggested that the apoptotic regulation of these genes did not occur for TP53. The P21 gene was shown to be mostly normal (70%); although, absence (6%) and underexpressions (24%) were also observed. Statistical analysis of the BCL-xL gene demonstrated significant differences between the tissues of the animals when compared to the cell cultures; however, to the other genes, no statistical difference was observed between the groups. Preliminarily, the results suggested the presence of alterations in the gene expressions of the TP53, P21, BAX, BCL-2 and BCL-xL leading to loss of function in these genes, which affect the tumorigenesis of CTVT.

scholarly journals Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

2020 ◽  
Author(s):  
Zeina R Al Sayed ◽  
Robin Canac ◽  
Bastien Cimarosti ◽  
Carine Bonnard ◽  
Jean-Baptiste Gourraud ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Electrical Conduction ◽  
Sodium Current ◽  
Single Gene ◽  
Gene Mutations ◽  
Cardiac Conduction ◽  
Human Model ◽  
Loss Of Function ◽  
Cardiac Electrical Activity

Abstract Aims Several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Methods and results Using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Conclusion Altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases.

scholarly journals Inherited IL-18BP deficiency in human fulminant viral hepatitis

2019 ◽  
Vol 216 (8) ◽  
pp. 1777-1790 ◽  
Author(s):  
Serkan Belkaya ◽  
Eleftherios Michailidis ◽  
Cecilia B. Korol ◽  
Mohammad Kabbani ◽  
Aurélie Cobat ◽  
...  
Keyword(s):  
Viral Hepatitis ◽  
Cell Activation ◽  
Hepatitis A Virus ◽  
Nk Cell ◽  
Single Gene ◽  
Loss Of Function ◽  
Homozygous State ◽  
Inborn Errors ◽  
Fulminant Viral Hepatitis

Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

scholarly journals The Coexistence of a Novel Inactivating Mutant Thyrotropin Receptor Allele with Two Thyroid Peroxidase Mutations: A Genotype-Phenotype Correlation

2011 ◽  
Vol 96 (6) ◽  
pp. E1001-E1006 ◽  
Author(s):  
Chutintorn Sriphrapradang ◽  
Yardena Tenenbaum-Rakover ◽  
Mia Weiss ◽  
Marla S. Barkoff ◽  
Osnat Admoni ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Gene Mutations ◽  
Structure And Function ◽  
Compound Heterozygote ◽  
Thyroid Peroxidase ◽  
Thyrotropin Receptor ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
And Function

Context: TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals. Objectives: The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual. Patients and Methods: Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs. Results: A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264S TSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation. Conclusions: TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.

scholarly journals Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1943
Author(s):  
Carol M. Amato ◽  
Jennifer D. Hintzsche ◽  
Keith Wells ◽  
Allison Applegate ◽  
Nicholas T. Gorden ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Gene Mutations ◽  
Enrichment Analysis ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Nfkb Activation ◽  
Pre Treatment

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NFkB, were found exclusively in the responders. Mutations in NKBIE-related genes were also enriched in the responder group compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the TNFalpha signaling via NFkB pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro NFkB activity assays indicated that the G34E variant caused loss-of-function of NFKBIE, and resulted in activation of NFkB signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB-related genes should be considered.

scholarly journals Molecular Basis of Thyroid Dyshormonogenesis: Genetic Screening in Population-Based Japanese Patients

2011 ◽  
Vol 96 (11) ◽  
pp. E1838-E1842 ◽  
Author(s):  
Satoshi Narumi ◽  
Koji Muroya ◽  
Yumi Asakura ◽  
Masanori Aachi ◽  
Tomonobu Hasegawa
Keyword(s):  
Single Gene ◽  
Population Based ◽  
Single Amino Acid ◽  
Thyroid Peroxidase ◽  
Loss Of Function ◽  
Phenotypic Spectrum ◽  
Thyroid Hormone Biosynthesis ◽  
Thyroid Dyshormonogenesis ◽  
Functional Snp

Abstract Context: Inborn errors of thyroid hormone biosynthesis are collectively referred to as thyroid dyshormonogenesis (DH). Seven genes have been implicated in DH, including the dual oxidase 2 gene (DUOX2), the thyroglobulin gene (TG), and the thyroid peroxidase gene (TPO). Objective: We aimed to define the prevalence and phenotypic spectrum of DH with single gene mutations. Subjects and Methods: A population-based cohort of 102 patients with permanent congenital hypothyroidism was enrolled. Fourteen were diagnosed as DH and were analyzed for the seven causative genes including DUOX2, TG, and TPO. Several common mutations were screened in the remaining 88 patients. Pathogenicity of single amino acid mutations was verified in vitro. Results: We identified four, five, and two patients with seemingly biallelic mutations in DUOX2, TG, and TPO, respectively. We also found two patients having one heterozygous DUOX2 mutation and one uncommon single-nucleotide polymorphism (SNP) p.H678R (rs57659670, allele frequency 0.035) and another two patients with homozygous p.H678R. Expression experiments and RT-PCR revealed that p.H678R is a functional SNP with theoretical 40% loss of function, supporting a role of p.H678R in the onset of DH. As for clinical phenotypes, patients with inactive DUOX2 alleles (mutations and/or p.H678R) showed characteristic time-dependent improvement of thyroid function and morphology. All three evaluated patients had a negative result in the perchlorate test. Conclusions: Mutations (or a functional SNP) in DUOX2, TG, or TPO were observed in 93% (95% confidence interval = 70–99%) of DH patients. Inactive DUOX2 alleles cause a broader phenotypic spectrum than currently accepted.

scholarly journals Cutting down the time to identify challenging tumor therapeutic targets and drug combinations using synthetic lethal approaches

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 308 ◽  
Author(s):  
John S. Lazo
Keyword(s):  
Drug Targets ◽  
Gene Mutations ◽  
Cancer Therapeutics ◽  
Drug Combinations ◽  
Cancer Drug ◽  
Loss Of Function ◽  
Synthetic Lethal ◽  
Optimal Drug

Cancer drug discoverers and developers are blessed and cursed with a plethora of drug targets in the tumor cells themselves and the surrounding stromal elements. This bounty of targets has, at least in part, inspired the rapid increase in the number of clinically available small-molecule, biological, and cellular therapies for solid and hematological malignancies. Among the most challenging questions in cancer therapeutics, especially for small molecules, is how to approach loss-of-function gene mutations or deletions that encode tumor suppressors. A second mounting question is what are the optimal drug combinations. This article will briefly review the recent advances in exploiting in vitro and in vivo synthetic lethal screens to expose cancer pharmacological targets with the goal of developing new drug combinations.

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