scholarly journals Study of molecular basis of thyroid dysgenesis

2018 ◽  
Vol 14 (2) ◽  
pp. 64-71
Author(s):  
Nina A. Makretskaya ◽  
Olga B. Bezlepkina ◽  
Anna A. Kolodkina ◽  
Alexey V. Kiyaev ◽  
Evgeny V. Vasilyev ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Molecular Basis ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Ion Torrent ◽  
Loss Of Function ◽  
Thyroid Dysgenesis ◽  
Different Types ◽  
Generation Sequencing ◽  
Tsh Levels

Congenital hypothyroidism is a heterogeneous group of diseases, which is manifested by loss of function of the thyroid gland that affects infants from birth. 80–85% of cases are due to different types of thyroid dysgenesis. 5 genes have been described that are involved in the pathogenesis of thyroid dysgenesis: TSHR, PAX8, FOXE1, NKX2-1, NKX2-5. Aims. To evaluate the prevalence of mutations in the genes TSHR, PAX8, FOXE1, NKX2-1, NKX2-5 among patients with severe congenital hypothyroidism. Materials and methods. 161 patients (64 boys, 97 girls) with congenital hypothyroidism (TSH levels at neonatal screening or retesting greater than 90 mU/l) were included in the study. 138 subjects had different variants of thyroid dysgenesis, and 23 patients had normal volume of the gland. A next generation sequencing was used for molecular-genetic analysis. Sequencing was performed using PGM semiconductor sequencer (Ion Torrent, Life Technologies, USA) and a panel “Hypothyroidism” (Custom DNA Panel). Assessment of the pathogenicity of sequence variants were carried out according to the latest international guidelines (ACMG, 2015). Results. 13 patients had variants in thyroid dysgenesis genes (8,1%, 13/161): TSHR, n = 6; NKX2-1, n = 3; NKX2-5, n = 1; PAX8, n = 3; FOXE1, n = 0. Conclusions. Mutations in thyroid dysgenesis genes are a rare pathology. The majority of variants among our patients were identified in TSHR.

scholarly journals Evaluation of Ion Torrent next-generation sequencing for thalassemia diagnosis

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052096777
Author(s):  
Peisong Chen ◽  
Xuegao Yu ◽  
Hao Huang ◽  
Wentao Zeng ◽  
Xiaohong He ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Ion Torrent ◽  
Next Generation ◽  
Large Deletions ◽  
Different Types ◽  
Variant Detection ◽  
Polymerase Chain ◽  
Next Generation Sequencing Ngs ◽  
Accuracy And Repeatability ◽  
Generation Sequencing

Introduction To evaluate a next-generation sequencing (NGS) workflow in the screening and diagnosis of thalassemia. Methods In this prospective study, blood samples were obtained from people undergoing genetic screening for thalassemia at our centre in Guangzhou, China. Genomic DNA was polymerase chain reaction (PCR)-amplified and sequenced using the Ion Torrent system and results compared with traditional genetic analyses. Results Of the 359 subjects, 148 (41%) were confirmed to have thalassemia. Variant detection identified 35 different types including the most common. Identification of the mutational sites by NGS were consistent with those identified by Sanger sequencing and Gap-PCR. The sensitivity and specificities of the Ion Torrent NGS were 100%. In a separate test of 16 samples, results were consistent when repeated ten times. Conclusion Our NGS workflow based on the Ion Torrent sequencer was successful in the detection of large deletions and non-deletional defects in thalassemia with high accuracy and repeatability.

scholarly journals A Novel Mutation of ATP7B Gene in a Case of Wilson Disease

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 123
Author(s):  
Cigdem Yuce Kahraman ◽  
Ali Islek ◽  
Abdulgani Tatar ◽  
Özlem Özdemir ◽  
Adil Mardinglu ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Compound Heterozygous ◽  
Atp7b Gene ◽  
Loss Of Function ◽  
Clinical Presentations ◽  
The Family ◽  
The Brain

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.

scholarly journals Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 308-313 ◽  
Author(s):  
WF Bahou ◽  
EJ Bowie ◽  
DN Fass ◽  
D Ginsburg
Keyword(s):  
Von Willebrand Factor ◽  
Molecular Basis ◽  
Gene Deletion ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Von Willebrand Disease ◽  
Molecular Defect ◽  
Human Disorder ◽  
Von Willebrand ◽  
Willebrand Factor

von Willebrand disease (vWD), one of the most common bleeding disorders in humans, is manifested as a quantitative or qualitative defect in von Willebrand factor (vWF), an adhesive glycoprotein (GP) with critical hemostatic functions. Except for the rare severely affected patient with a gene deletion as etiology of the disease, the molecular basis for vWD is not known. We studied the molecular basis for vWD in a breeding colony of pigs with a disease closely resembling the human disorder. The porcine vWF gene is similar in size and complexity to its human counterpart, and no gross gene deletion or rearrangement was evident as the pathogenesis of porcine vWD. A restriction fragment- length polymorphism (RFLP) within the porcine vWF gene was identified with the restriction endonuclease HindIII, and 22/35 members of the pedigree were analyzed for the polymorphic site. Linkage between the vWF locus and the vWD phenotype was established with a calculated LOD score of 5.3 (1/200,000 probability by chance alone), with no crossovers identified. These findings indicate that porcine vWD is due to a molecular defect within (or near) the vWF locus, most likely representing a point mutation or small insertion/deletion within the vWF gene.

scholarly journals Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 308-313 ◽  
Author(s):  
WF Bahou ◽  
EJ Bowie ◽  
DN Fass ◽  
D Ginsburg
Keyword(s):  
Von Willebrand Factor ◽  
Molecular Basis ◽  
Gene Deletion ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Von Willebrand Disease ◽  
Molecular Defect ◽  
Human Disorder ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand disease (vWD), one of the most common bleeding disorders in humans, is manifested as a quantitative or qualitative defect in von Willebrand factor (vWF), an adhesive glycoprotein (GP) with critical hemostatic functions. Except for the rare severely affected patient with a gene deletion as etiology of the disease, the molecular basis for vWD is not known. We studied the molecular basis for vWD in a breeding colony of pigs with a disease closely resembling the human disorder. The porcine vWF gene is similar in size and complexity to its human counterpart, and no gross gene deletion or rearrangement was evident as the pathogenesis of porcine vWD. A restriction fragment- length polymorphism (RFLP) within the porcine vWF gene was identified with the restriction endonuclease HindIII, and 22/35 members of the pedigree were analyzed for the polymorphic site. Linkage between the vWF locus and the vWD phenotype was established with a calculated LOD score of 5.3 (1/200,000 probability by chance alone), with no crossovers identified. These findings indicate that porcine vWD is due to a molecular defect within (or near) the vWF locus, most likely representing a point mutation or small insertion/deletion within the vWF gene.

Molecular genetic analysis of the Drosophila melanogaster gene absent, small or homeotic discs1 (ash1).

Genetics ◽  
1994 ◽  
Vol 137 (4) ◽  
pp. 1027-1038 ◽  
Author(s):  
N A Tripoulas ◽  
E Hersperger ◽  
D La Jeunesse ◽  
A Shearn
Keyword(s):  
Imaginal Disc ◽  
Gamma Ray ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
P Element ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Larval Stages ◽  
Cytogenetic Location ◽  
Egg Chambers

Abstract The absent, small or homeotic discs1 gene (ash1) is one of the trithorax set of genes. Recessive loss of function mutations in ash1 cause homeotic transformations of imaginal disc derived tissue which resemble phenotypes caused by partial loss or gain of function mutations in genes of the Antennapedia Complex and bithorax Complex. F2 screens were used to isolate P element insertion alleles and EMS-induced alleles of ash1, including one temperature-sensitive allele, and an F1 screen was used to isolate gamma-ray-induced alleles. Analysis of ash1 mutant flies that survive until the adult stage indicates that not only imaginal disc- and histoblast-derived tissues are affected but also that oogenesis requires ash1 function. Mutations in the gene brahma (brm) which also is one of the trithorax set of genes interact with mutations in ash1 such that non-lethal ash1 +/+ brm double heterozygotes have a high penetrance of homeotic transformations in specific imaginal disc- and histoblast-derived tissues. The cytogenetic location of ash1 was determined to be 76B6-11 by the breakpoint of a translocation recovered in the F1 screen. The gene Shal, which is located cytogenetically nearby ash1, was used to initiate an 84-kb genomic walk within which the ash1 gene was identified. The ash1 gene encodes a 7.5-kb transcript that is expressed throughout development but is present at higher levels during the embryonic and pupal stages than during the larval stages. During the larval stages the transcript accumulates primarily in imaginal discs. During oogenesis the transcript accumulates in the nurse cells of developing egg chambers.

scholarly journals Characterization of a Novel Loss of Function Mutation of PAX8 in a Familial Case of Congenital Hypothyroidism with In-Place, Normal-Sized Thyroid

2004 ◽  
Vol 89 (9) ◽  
pp. 4285-4291 ◽  
Author(s):  
Laurent Meeus ◽  
Brigitte Gilbert ◽  
Catherine Rydlewski ◽  
Jasmine Parma ◽  
Anne Lienhardt Roussie ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Congenital Hypothyroidism ◽  
Novel Mutation ◽  
Gene Promoter ◽  
Loss Of Function ◽  
Thyroid Dysgenesis ◽  
Cis Element ◽  
Ability To Act ◽  
Pax8 Gene ◽  
Functional Analyses

Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000–4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.

Retrospective evaluation of patients with X-linked adrenoleukodystrophy with a wide range of clinical presentations: a single center experience

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Asburce Olgac ◽  
Çiğdem Seher Kasapkara ◽  
Betül Derinkuyu ◽  
Deniz Yüksel ◽  
Semra Çetinkaya ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Neurological Deterioration ◽  
Loss Of Function ◽  
Single Center ◽  
Hematopoietic Stem ◽  
Initial Symptoms ◽  
Wide Range ◽  
Neurological System

Abstract Objectives X-linked adrenoleukodystrophy (X-ALD), is a peroxisomal inborn error of metabolism caused due to the loss of function variants of ABCD1 gene that leads to accumulation of very long chain fatty acids (VLCFAs) in several tissues including the neurological system. Childhood cerebral X-ALD (CCALD) is the most common and severe form of X-ALD, if left untreated. Allogenic hematopoietic stem cell transplantation (HSCT) is the only available therapy that halts neurological deterioration in CCALD. We present 12 patients with several subtypes of X-ALD that were followed-up in a single center. Methods Data of 12 patients diagnosed with X-ALD were documented retrospectively. Demographics, age of onset, initial symptoms, endocrine and neurological findings, VLCFA levels, neuroimaging data, molecular genetic analysis of ABCD1 gene, and disease progress were documented. Results Mean age of initiation of symptoms was 7.9 years and mean age of diagnosis was 10.45 years. Eight patients had the CCALD subtype, while two had the cerebral form of AMN, one had the adult form of cerebral ALD, and one patient had the Addison only phenotype. The most common initial symptoms involved the neurological system. Loes scores varied between 0 and 12. Seven patients with CCALD underwent HSCT, among them three patients died. The overall mortality rate was 25%. Conclusions Patients with X-ALD should be carefully followed up for cerebral findings and progression, since there is no genotype–phenotype correlation, and the clinical course cannot be predicted by family history. HSCT is the only available treatment option for patients with neurological deterioration.

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