scholarly journals The p.A2215D Thyroglobulin Gene Mutation Leads to Deficient Synthesis and Secretion of the Mutated Protein and Congenital Hypothyroidism with Wide Phenotype Variation

2009 ◽  
Vol 94 (8) ◽  
pp. 2938-2944 ◽  
Author(s):  
Viviane Pardo ◽  
Jussara Vono-Toniolo ◽  
Ileana G. S. Rubio ◽  
Meyer Knobel ◽  
Roberta F. Possato ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Endoplasmic Reticulum ◽  
Thyroid Hormone ◽  
Congenital Hypothyroidism ◽  
Gene Mutations ◽  
Cell System ◽  
Expression Vectors ◽  
Compound Heterozygous ◽  
Novel Mutations ◽  
Phenotype Variation

Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.

scholarly journals Thyroid Gene Mutations in Pregnant and Breastfeeding Women Diagnosed With Transient Congenital Hypothyroidism: Implications for the Offspring’s Health

2021 ◽  
Vol 12 ◽  
Author(s):  
Maria C. Opazo ◽  
Juan Carlos Rivera ◽  
Pablo A. Gonzalez ◽  
Susan M. Bueno ◽  
Alexis M. Kalergis ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Congenital Hypothyroidism ◽  
Gene Mutations ◽  
Genetic Variations ◽  
Hormone Deficiency ◽  
Iodide Transport ◽  
Transport Defect ◽  
Pregnancy And Lactation ◽  
Transient Congenital Hypothyroidism

Fetus and infants require appropriate thyroid hormone levels and iodine during pregnancy and lactation. Nature endorses the mother to supply thyroid hormones to the fetus and iodine to the lactating infant. Genetic variations on thyroid proteins that cause dyshormonogenic congenital hypothyroidism could in pregnant and breastfeeding women impair the delivery of thyroid hormones and iodine to the offspring. The review discusses maternal genetic variations in thyroid proteins that, in the context of pregnancy and/or breastfeeding, could trigger thyroid hormone deficiency or iodide transport defect that will affect the proper development of the offspring.

Novel DIO1 gene mutation acting as phenotype modifier for novel compound heterozygous TPO gene mutations causing congenital hypothyroidism

Thyroid ◽  
2021 ◽  
Author(s):  
Aryel E Furman ◽  
Zeina Hannoush ◽  
Francisco X Barrera Echegoyen ◽  
Alexandra M Dumitrescu ◽  
Samuel Refetoff ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Congenital Hypothyroidism ◽  
Gene Mutations ◽  
Compound Heterozygous

Functional analysis of thyroid peroxidase gene mutations resulting in congenital hypothyroidism

2020 ◽  
Vol 93 (4) ◽  
pp. 499-507 ◽  
Author(s):  
Defa Zhao ◽  
Yang Li ◽  
Zhongyan Shan ◽  
Weiping Teng ◽  
Jing Li ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Congenital Hypothyroidism ◽  
Gene Mutations ◽  
Thyroid Peroxidase ◽  
Peroxidase Gene

scholarly journals Identification of Novel Mutation Sites in DNAH1 of Multiple Morphological Anomalies of the Flagella Patients

2021 ◽  
Author(s):  
Xiong Wang ◽  
Yan-Wei Sha ◽  
Xing-shen Zhu ◽  
Xiao-ya Zhang ◽  
Yuan-qing Cui ◽  
...  
Keyword(s):  
Intracytoplasmic Sperm Injection ◽  
Novel Mutation ◽  
Gene Mutations ◽  
The Body ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Novel Mutations ◽  
Genetic Landscape ◽  
Morphological Anomalies ◽  
The Impact

Abstract BackgroundMultiple morphological anomalies of the sperm flagella (MMAF) is a term used to describe abnormalities in sperm morphology, which lead to primary infertility in males. Intracytoplasmic sperm injection (ICSI) is an effective treatment for MMAF. However, ICSI failure rates remain high in MMAF patients. Our purpose was to investigate novel gene mutations in a cohort of nineteen patients with MMAF and assess the impact of these mutations on assisted reproductive therapy.MethodsWe recruited nineteen infertile patients with MMAF and twenty healthy men with proven fertility at the Affiliated Yantai Yuhuangding Hospital of Qingdao University. The morphology of the spermatozoa was observed using Papanicolaou staining and the ultrastructure of the spermatozoa was inspected using transmission electron microscopy. Gene mutations were evaluated using whole-exome sequencing and novel mutations were further validated in patients and their parents using Sanger sequencing. The effect of these novel mutation sites on the expression of DNAH1 was analysed using immunofluorescence, and the effect of these novel mutations on pregnancy outcome was analysed using intracytoplasmic sperm injection (ICSI). ResultsSpermatozoa from 19 patients presented with a typical MMAF phenotype including severe ultrastructural defects. We identified ten novel mutation sites in the DNAH1 locus from six of these patients, none of which were identified in DNAH1 or the other MMAF-related genes from the twenty men with proven fertility. In the sperm from these patients, DNAH1 was absent. Three patients with DNAH1 mutation who underwent intracytoplasmic sperm injection (ICSI) had a good outcome. ConclusionHere, we describe several novel compound heterozygous mutations and a novel homozygous mutation in DNAH1 from six independent MMAF patients. This study adds to the body of knowledge surrounding the genetic landscape of MMAF and DNAH1 improving our ability to diagnose and treat MMAF efficiently.

scholarly journals Analysis of Mutation Spectra of 28 Pathogenic Genes Associated With Congenital Hypothyroidism in the Chinese Han Population

2021 ◽  
Vol 12 ◽  
Author(s):  
Miao Huang ◽  
Xiyan Lu ◽  
Guoqing Dong ◽  
Jianxu Li ◽  
Chengcong Chen ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Detection Rate ◽  
Target Genes ◽  
Clinical Manifestations ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Chinese Han ◽  
High Detection Rate ◽  
Published Evidence ◽  
Pathogenic Genes

PurposeCongenital hypothyroidism (CH) is the most common neonatal endocrine disease; its early detection ensures successful treatment and prevents complications. However, its molecular etiology remains unclear.MethodsWe used second-generation sequencing to detect 28 pathogenic genes in 15 Chinese Han patients with CH in Shenzhen, China, and analyzed the genetic pattern of the pathogenic genes through their pedigrees. The pathogenicity assessment of gene mutations was performed based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines, inheritance models, and published evidence.ResultsMutations in several target genes were identified in 14 of 15 patients (93.33%); these mutations were distributed in eight genes (DUOX2, DUOXA2, TPO, TG, TSHR, FOXE1, KDM6A, and POU1F1). DUOX2 exhibited the highest mutation frequency (44%, 11/25), followed by TPO (16%, 4/25) and TG (16%, 4/25). DUOX2 exhibited the highest biallelic mutation (7/15). Eight out of 25 variants verified by the ACMG guidelines were classified as pathogenic (P, category 1) or possibly pathogenic (LP, Type 2), namely six variants of DUOX2, and one variant of TPO and DUOXA2. Five new mutations were detected: one in DUOX2, which was located in the splicing region of mRNA (c.1575-1G>A), three new missense mutants, p.A291T, p.R169W, and p. S1237dup, and one new TPO missense variant c.2012G>T (p.W671L). The main criteria for determining the genotype–phenotype relationship were a diagnostic detection rate of 53.33% (8/15) and combination of three or more gene mutations.ConclusionsCH gene mutations in the population may be mainly manifested in genes influencing thyroid hormone synthesis, such as DUOX2 compound heterozygous mutations, which exhibited a high detection rate. The clinical manifestations are diverse, and mainly include transient CH. Therefore, genetic screening is recommended for CH patients to determine the correlation between clinical phenotypes and gene mutations, which will assist in clinical management.

Five novel ALMS1 gene mutations in six patients with Alström syndrome

2018 ◽  
Vol 31 (6) ◽  
pp. 681-687 ◽  
Author(s):  
Suna Kılınç ◽  
Didem Yücel-Yılmaz ◽  
Aylin Ardagil ◽  
Süheyla Apaydın ◽  
Diana Valverde ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Autosomal Recessive ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Novel Mutations ◽  
Alström Syndrome ◽  
Mutational Screening ◽  
Clinical Presentations ◽  
Alstrom Syndrome ◽  
Over Time

Abstract Background: Alström syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene. Methods: We describe the clinical and five novel mutational screening findings in six patients with Alström syndrome from five families in a single center with distinct clinical presentations of this condition. Results: Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alström syndrome previously. Conclusions: Early diagnosis of Alström syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage.

scholarly journals Functional analysis of a transactivation domain in the thyroid hormone beta receptor.

1994 ◽  
Vol 269 (49) ◽  
pp. 31157-31161
Author(s):  
Y Tone ◽  
T N Collingwood ◽  
M Adams ◽  
V K Chatterjee
Keyword(s):  
Functional Analysis ◽  
Thyroid Hormone ◽  
Transactivation Domain ◽  
Beta Receptor

scholarly journals Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Jong Seop Kim ◽  
Hyoungseok Jeon ◽  
Hyeran Lee ◽  
Jung Min Ko ◽  
Yonghwan Kim ◽  
...  
Keyword(s):  
Hip Dysplasia ◽  
Large Deletion ◽  
Compound Heterozygous ◽  
Radial Head Dislocation ◽  
Sequencing Data ◽  
Novel Mutations ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Carpal Coalition

AbstractAn 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38–60, which was challenging to detect.

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