scholarly journals Pendred Syndrome in Two Galician Families: Insights into Clinical Phenotypes through Cellular, Genetic, and Molecular Studies

2008 ◽  
Vol 93 (1) ◽  
pp. 267-277 ◽  
Author(s):  
Fernando Palos ◽  
María E. R. García-Rendueles ◽  
David Araujo-Vilar ◽  
Maria Jesús Obregon ◽  
Rosa Maria Calvo ◽  
...  
Keyword(s):  
Outcome Measures ◽  
Molecular Mechanisms ◽  
Novel Mutation ◽  
Thyroid Tissue ◽  
Iodine Uptake ◽  
Incomplete Penetrance ◽  
Pendred Syndrome ◽  
Iodothyronine Deiodinase ◽  
Large Goiter ◽  
Iodine Retention

Abstract Context: We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter. Objective: Our objective was to identify the mutations causing PS and molecular mechanisms underlying the thyroid phenotypes. Interventions: Interventions included extraction of DNA and of thyroid tissue. Patients: Propositi and 10 members of the two families participated in the study. Main Outcome Measures: Main outcome measures included SLC26A4 gene analysis, deiodinase activities in thyroid tissue, and c.416–1G→A effects on SLC26A4 splicing. In addition, a primary PS thyrocyte culture, T-PS2, was obtained from propositus B and compared with another culture of normal human thyrocytes, NT, by Western blotting, confocal microscopy, and iodine uptake kinetics. Results: Proposita A was heterozygous for c.578C→T and c.279delT, presented with goiter, and had normal TSH and FT3 but low FT4 attributable to high type 1 and type 2 iodothyronine deiodinase activities in the goiter. Propositus B bore c.279delT and a novel mutation c.416–1G→A; some deaf relatives were homozygous for c.416–1G→A but did not present goiter. The c.279delT mutation was associated with identical haplotype in the two families. T-PS2 showed truncated pendrin retained intracellularly and high iodine uptake with low efflux leading to iodine retention. Conclusions: c.279delT is a founder mutation in Galicia. Proposita A adapted to poor organification by increasing deiodinase activities in the goiter, avoiding hypothyroidism. Lack of goiter in subjects homozygous for c.416–1G→A was due to incomplete penetrance allowing synthesis of some wild-type pendrin. Intracellular iodine retention, as seen in T-PS2, could play a role in thyroid alterations in PS.

Identification of Differentially Expressed Genes Associated with Papillary Thyroid Carcinoma

2020 ◽  
Vol 23 (6) ◽  
pp. 546-553
Author(s):  
Hongyuan Cui ◽  
Mingwei Zhu ◽  
Junhua Zhang ◽  
Wenqin Li ◽  
Lihui Zou ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Differentially Expressed Genes ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Mrna Level ◽  
Thyroid Tissue ◽  
Differentially Expressed ◽  
Thyroid Tumors ◽  
Papillary Thyroid

Objective: Next-generation sequencing (NGS) was performed to identify genes that were differentially expressed between normal thyroid tissue and papillary thyroid carcinoma (PTC). Materials & Methods: Six candidate genes were selected and further confirmed with quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry in samples from 24 fresh thyroid tumors and adjacent normal tissues. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was used to investigate signal transduction pathways of the differentially expressed genes. Results: In total, 1690 genes were differentially expressed between samples from patients with PTC and the adjacent normal tissue. Among these, SFRP4, ZNF90, and DCN were the top three upregulated genes, whereas KIRREL3, TRIM36, and GABBR2 were downregulated with the smallest p values. Several pathways were associated with the differentially expressed genes and involved in cellular proliferation, cell migration, and endocrine system tumor progression, which may contribute to the pathogenesis of PTC. Upregulation of SFRP4, ZNF90, and DCN at the mRNA level was further validated with RT-PCR, and DCN expression was further confirmed with immunostaining of PTC samples. Conclusion: These results provide new insights into the molecular mechanisms of PTC. Identification of differentially expressed genes should not only improve the tumor signature for thyroid tumors as a diagnostic biomarker but also reveal potential targets for thyroid tumor treatment.

scholarly journals New PAX2 Mutation Associated with Polycystic Kidney Disease: A Case Report

2021 ◽  
Vol 15 ◽  
pp. 117955652199235
Author(s):  
Jessica Maria Forero-Delgadillo ◽  
Vanessa Ochoa ◽  
Natalia Duque ◽  
Jaime Manuel Restrepo ◽  
Hernando Londoño ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Renal Cysts ◽  
Renal Dysplasia ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Incomplete Penetrance ◽  
Wide Range ◽  
Stage Renal Disease

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage renal disease in children. Diagnosis by genetic testing has proven challenging due to its genetic and phenotypic heterogeneity, as well as incomplete penetrance. We report a case on a 16-months old female with a history of renal cysts and a PAX2 mutation. Case presentation: The patient presented with a prenatal diagnosis of Potter sequence and a postnatal diagnosis of renal cysts. An ultrasound at 20 weeks gestation revealed right renal agenesis and possible left renal dysplasia. Post natal genetic analyses identified a novel mutation in PAX2. Conclusion: Cystic kidney disease is often underdiagnosed due to its variable expressivity and wide range of clinical manifestations; PAX2 genetic screening should be considered for all patients with CAKUT.

scholarly journals Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Matrin-3 Variant 5

2020 ◽  
Vol 11 ◽  
Author(s):  
Madelyn Castro ◽  
Nisha Venkateswaran ◽  
Samuel T. Peters ◽  
David R. Deyle ◽  
Matthew Bower ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Early Onset ◽  
Messenger Rna ◽  
Dna Analysis ◽  
Novel Mutation ◽  
Full Length ◽  
Incomplete Penetrance ◽  
Significant Past Medical History ◽  
Degree Relative ◽  
Matrin 3

Frontotemporal dementia (FTD) rarely occurs in individuals under the age of 30, and genetic causes of early-onset FTD are largely unknown. The current report follows a 27 year-old patient with no significant past medical history presenting with two years of progressive changes in behavior, rushed speech, verbal aggression, and social withdrawal. MRI and FDG-PET imaging of the brain revealed changes maximally in the frontal and temporal lobes, which along with the clinical features, are consistent with behavioral variant FTD. Next generation sequencing of a panel of 28 genes associated with dementia and amyotrophic lateral sclerosis (ALS) initially revealed a duplication of exon 15 in Matrin-3 (MATR3). Whole genome sequencing determined that this genetic anomaly was, in fact, a sequence corresponding with full-length MATR3 variant 5 inserted into chromosome 12, indicating retrotransposition from a messenger RNA intermediate. To our knowledge, this is a novel mutation of MATR3, as the majority of mutations in MATR3 linked to FTD-ALS are point mutations. Genomic DNA analysis revealed that this mutation is also present in one unaffected first-degree relative and one unaffected second-degree relative. This suggests that the mutation is either a disease-causing mutation with incomplete penetrance, which has been observed in heritable FTD, or a benign variant. Retrotransposons are not often implicated in neurodegenerative diseases; thus, it is crucial to clarify the potential role of this MATR3 variant 5 retrotransposition in early-onset FTD.

scholarly journals MEF2A Regulates the MEG3-DIO3 miRNA Mega Cluster-Targeted PP2A Signaling in Bovine Skeletal Myoblast Differentiation

2019 ◽  
Vol 20 (11) ◽  
pp. 2748 ◽  
Author(s):  
Yaning Wang ◽  
Chugang Mei ◽  
Xiaotong Su ◽  
Hongbao Wang ◽  
Wucai Yang ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Molecular Mechanisms ◽  
Regulatory Subunit ◽  
Myoblast Differentiation ◽  
Mirna Cluster ◽  
Skeletal Myoblast ◽  
Iodothyronine Deiodinase ◽  
Luciferase Activity Assay ◽  
Phosphatase 2A ◽  
Protein Phosphatase 2

Understanding the molecular mechanisms of skeletal myoblast differentiation is essential for studying muscle developmental biology. In our previous study, we reported that knockdown of myocyte enhancer factor 2A (MEF2A) inhibited myoblast differentiation. Here in this study, we further identified that MEF2A controlled this process through regulating the maternally expressed 3 (MEG3)—iodothyronine deiodinase 3 (DIO3) miRNA mega cluster and protein phosphatase 2A (PP2A) signaling. MEF2A was sufficient to induce MEG3 expression in bovine skeletal myoblasts. A subset of miRNAs in the MEG3-DIO3 miRNA cluster was predicted to target PP2A subunit genes. Consistent with these observations, MEF2A regulated PP2A signaling through its subunit gene protein phosphatase 2 regulatory subunit B, gamma (PPP2R2C) during bovine myoblast differentiation. MiR-758 and miR-543 in the MEG3-DIO3 miRNA cluster were down-regulated in MEF2A-depleted myocytes. Expression of miR-758 and miR-543 promoted myoblast differentiation and repressed PPP2R2C expression. Luciferase activity assay showed that PPP2R2C was post-transcriptionally targeted by miR-758 and miR-543. Taken together, these results reveal that the MEG3-DIO3 miRNAs function at downstream of MEF2A to modulate PP2A signaling in bovine myoblast differentiation.

scholarly journals Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

2007 ◽  
Vol 92 (4) ◽  
pp. 1451-1457 ◽  
Author(s):  
Yasuhiko Kanou ◽  
Akira Hishinuma ◽  
Katsuhiko Tsunekawa ◽  
Koji Seki ◽  
Yutaka Mizuno ◽  
...  
Keyword(s):  
Thyroid Gland ◽  
Intracellular Transport ◽  
Mrna Level ◽  
Thyroid Tissue ◽  
Compound Heterozygous ◽  
Free T4 ◽  
Iodothyronine Deiodinase ◽  
Normal Thyroid ◽  
Thyroid Glands

Abstract Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown. Objective: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis. Design: We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue. Results: Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios. Conclusion: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.

scholarly journals Demonstration of reduced in vivo surface expression of activating mutant thyrotrophin receptors in thyroid sections

2002 ◽  
pp. 163-171 ◽  
Author(s):  
M Sequeira ◽  
B Jasani ◽  
D Fuhrer ◽  
M Wheeler ◽  
M Ludgate
Keyword(s):  
Molecular Mechanisms ◽  
Thyroid Tissue ◽  
Surface Expression ◽  
Germline Mutations ◽  
Antigen Retrieval ◽  
Graves Disease ◽  
Paraffin Sections ◽  
Gain Of Function

OBJECTIVE: Thyroid function and growth are controlled by TSH. Hyperthyroidism can be due to Graves' Disease (GD), in which thyroid-stimulating antibodies mimic TSH, or gain-of-function mutations in the TSH receptor (TSHR). These activating mutations have poor surface expression when assessed in non-thyroidal cells in vitro but nothing is known of their in vivo behaviour. Several TSHR antibodies have been produced but none has been applied to thyroid paraffin sections. This study aimed to develop a technique suitable for use on paraffin sections and apply it to investigate TSHR expression in thyroids harbouring activating TSHR germline mutations compared with normal and GD thyroids. DESIGN AND METHODS: Immunocytochemistry coupled with antigen retrieval, using a spectrum of antibodies to the TSHR, was applied to paraffin sections of GD thyroid tissue. Subsequently, TSHR immunoreactivity was examined in three normal thyroids, three patients with GD and three patients with familial hyperthyroidism, due to different gain-of-function TSHR germline mutations, using the optimised protocol. RESULTS: Two antibodies, A10 and T3-495, to the extracellular domain (ECD) and membrane spanning region (MSR) of the TSHR respectively, produced specific basolateral staining of thyroid follicular cells. In normal and GD thyroids, basolateral staining with T3-495 was generally more intense than with A10, suggesting a possible surfeit of MSR over ECD. Graves' Disease thyroids have more abundant TSHR than normal glands. In contrast, thyroids harbouring gain-of-function mutations have the lowest expression in vivo, mirroring in vitro findings. CONCLUSIONS: The development of an immunocytochemical method applicable to paraffin sections has demonstrated that different molecular mechanisms causing hyperthyroidism result in the lowest (mutation) and highest (autoimmunity) levels of receptor at the thyrocyte surface.

scholarly journals Detection of a novel mutation G511T in the 530 loop in 16S rRNA in multi drugs resistant Mycobacterium tuberculosis isolated from Sudanese patients

2018 ◽  
Author(s):  
Yousif Mohammed Alfatih ◽  
Abeer Babiker Idris ◽  
Hadeel Gassim Hassan ◽  
Eman O M Nour ◽  
Nihad M A Elhaj ◽  
...  
Keyword(s):  
16S Rrna ◽  
Molecular Mechanisms ◽  
Novel Mutation ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
World Health ◽  
Bacterial Disease ◽  
Global Public Health ◽  
Mdr Tb ◽  
Health Organization

Background: Tuberculosis (TB) is a bacterial disease considered as a global public health emergency by the World Health Organization (WHO) since 1993. In Sudan, MDR-TB represents a growing threat and one of the most important challenges that faced national tuberculosis program to establish a comprehensive multidrug-resistant tuberculosis management system. Objective: To characterize the diversity and frequency of mutations in Sudanese MDR-TB strains isolated from Wad Madani, Al-Gadarif and Khartoum using 16S rRNA and phylogeny approach. Material and Methods: A total of 60 MDR-TB isolates from Wad-Madani, Al-Gadarif and Khartoum were tested with molecular LPA (Genotype MTBDR plus) and GeneXpert MTB/RIF assay and Spoligotyping to confirm their resistance to RIF and INH. Sequencing and phylogenetic analysis was carried out using in silico tools. Result: This study revealed the circulation of different Sudanese MDR-TB strains isolated from Wad Madani and Al-Gadarif belonging to two distinct common ancestors. Two isolates from Wad Madani (isolate3 and isolate11) found in one main group which characterized by a novel mutation G511T in the 530 loop. Conclusion: The recurrence of C217A mutation in Wad Madani (isolate11) indicates the spread of this mutation in Sudanese MDR-TB strains and the diversity of this inheritance leading to generate new G511T novel mutation. So, understanding the molecular characterization of resistance mechanisms in MD-TB can facilitate the early detection of resistance, the choice of appropriate treatment and ultimately the management of MD-TB transmission. Bioinformatics approaches provide helpful tools for analyzing molecular mechanisms of resistance in pathogens.

scholarly journals A CASE OF RARE INHERITED RESTRICTIVE CARDIOMYOPATHY CAUSED BY A NOVEL MUTATION IN MYH7 GENE

2021 ◽  
Vol 9 (09) ◽  
pp. 780-786
Author(s):  
Aya Belkhadir ◽  
◽  
Kamal Marzouki ◽  
Mohamed Aoudad ◽  
Amale Tazi Mezalek ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Gene Mutations ◽  
Restrictive Cardiomyopathy ◽  
Incomplete Penetrance ◽  
Patients At Risk ◽  
History Of ◽  
Pace Maker

Introduction: Inherited restrictive cardiomyopathy (RCM) is a rare cause of RCM associated with cytoskeletal and sarcoma gene mutations. We describe a case of inherited RCM due to MYH7s genetic mutation.Case description: A 66 year-old-woman was admitted for acute global heart failure. She had a family history of RCM with a mutation of MYH7 gene: sons sudden death at 30, one of her daughters who is 40 and grandson who is 1. The transthoracic cardiac ultrasound (TTE) showed a bi-atrial dilation, a non-dilated left ventricle (LV) non-hypertrophied. Genetic investigation found the same pathogenic missense mutation (c. 1477A>G in heterozygous state) in our patient and her daughter who has a non-obstructive hypertrophy cardiomyopathy (HCM).A few weeks later, our patient had a syncope on complete atrioventricular block. A triple chamber pace maker was installed. Discussion: Familial RCMs mutations are characterized by high allelic, genetic and phenotypic variability, with autosomal dominant inheritance and variable penetrance. This mutation is rarely found in RCM, it is usually reported in HCM (OMIM 160760). Genetic screening should be considered to identify patients at risk in families with suspected familial transmission. MYH7 mutations seem to be associated with severe phenotypes, earlier age of onset and more pejorative evolution than other mutations. Conclusion:The evaluation of familial RCM requires an understanding of its variable phenotypic expression and incomplete penetrance. RCM and HCM may coexist in the same family. Genetic testing for hereditary RCM should be considered when secondary causes have been excluded.

Human genetics and molecular mechanisms of vein of Galen malformation

2018 ◽  
Vol 21 (4) ◽  
pp. 367-374 ◽  
Author(s):  
Daniel Duran ◽  
Philipp Karschnia ◽  
Jonathan R. Gaillard ◽  
Jason K. Karimy ◽  
Mark W. Youngblood ◽  
...  
Keyword(s):  
Arteriovenous Malformation ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
De Novo ◽  
Phenotypic Variability ◽  
Interventional Neuroradiology ◽  
De Novo Mutation ◽  
Incomplete Penetrance ◽  
Vein Of Galen ◽  
Cerebrovascular Lesions

Vein of Galen malformations (VOGMs) are rare developmental cerebrovascular lesions characterized by fistulas between the choroidal circulation and the median prosencephalic vein. Although the treatment of VOGMs has greatly benefited from advances in endovascular therapy, including technical innovation in interventional neuroradiology, many patients are recalcitrant to procedural intervention or lack accessibility to specialized care centers, highlighting the need for improved screening, diagnostics, and therapeutics. A fundamental obstacle to identifying novel targets is the limited understanding of VOGM molecular pathophysiology, including its human genetics, and the lack of an adequate VOGM animal model. Herein, the known human mutations associated with VOGMs are reviewed to provide a framework for future gene discovery. Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation–arteriovenous malformation syndrome (RASA1) and hereditary hemorrhagic telangiectasia (ENG and ACVRL1). However, these mutations probably represent only a small fraction of all VOGM cases. Traditional genetic approaches have been limited in their ability to identify additional causative genes for VOGM because kindreds are rare, limited in patient number, and/or seem to have sporadic inheritance patterns, attributable in part to incomplete penetrance and phenotypic variability. The authors hypothesize that the apparent sporadic occurrence of VOGM may frequently be attributable to de novo mutation or incomplete penetrance of rare transmitted variants. Collaboration among treating physicians, patients’ families, and investigators using next-generation sequencing could lead to the discovery of novel genes for VOGM. This could improve the understanding of normal vascular biology, elucidate the pathogenesis of VOGM and possibly other more common arteriovenous malformation subtypes, and pave the way for advances in the diagnosis and treatment of patients with VOGM.

Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant

Rheumatology ◽  
2019 ◽  
Vol 59 (9) ◽  
pp. 2334-2339 ◽  
Author(s):  
Troels Herlin ◽  
Sofie E Jørgensen ◽  
Christian Høst ◽  
Patrick S Mitchell ◽  
Maria Hønholt Christensen ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Mononuclear Cells ◽  
Novel Mutation ◽  
Mucosal Inflammation ◽  
Inflammasome Activation ◽  
Incomplete Penetrance ◽  
Peripheral Blood Mononuclear ◽  
Pyrin Domain ◽  
Patient Pbmcs

Abstract Objectives Here we investigated a patient with inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, tooth abnormalities and, eczema to uncover the genetic and immunological basis of the disease. Methods On suspicion of an autoinflammatory condition, Sanger sequencing of nucleotide-binding oligomerization domain-like, leucine-rich repeat pyrin domain containing 1 (NLRP1) was performed and combined with an in vitro inflammasome reconstitution assay to measure caspase-1-mediated IL-1β cleavage, stimulation of patient peripheral blood mononuclear cells (PBMCs) and whole blood to measure IL-1β, IL-18 production and quantification of apoptosis-associated speck-like protein containing CARD (ASC) speck formation as a measure of inflammasome activation by flow cytometry. Results Sanger sequencing revealed a novel mutation (c.175G>C, p.A59P; NM_33004.4) in the inflammasome molecule NLRP1 segregating with disease, although with incomplete penetrance, in three generations. We found that patient PBMCs produced increased IL-1β in response to inflammatory stimuli, as well as increased constitutive levels of IL-18. Moreover, we demonstrate that expression of the identified NLRP1 A59P variant caused spontaneous IL-1β cleavage to mature IL-1β. In addition, patient PBMCs responded to NLRP1 stimulation with increased ASC speck formation as a reflection of elevated inflammasome activity. Conclusion We demonstrate that this novel NLRP1 A59P variant caused increased activation of the NLRP1 inflammasome, resulting in constitutively and inducibly elevated IL-1β and IL-18 synthesis. We suggest the NLRP1 mutation underlies the pathogenesis of this rare autoinflammatory dyskeratotic disease inherited in an autosomal dominant manner with incomplete penetrance in the patient and within the family for several generations.

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