Clinical and Genetic Analysis of a Compound Heterozygous Mutation in the Thyroglobulin Gene in a Chinese Twin Family With Congenital Goiter and Hypothyroidism

2012 ◽  
Vol 15 (1) ◽  
pp. 126-132 ◽  
Author(s):  
Shiguo Liu ◽  
Shasha Zhang ◽  
Wenjie Li ◽  
Aiqing Zhang ◽  
Fengguang Qi ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Congenital Hypothyroidism ◽  
High Performance ◽  
Stop Codon ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Chinese Han ◽  
Congenital Goiter ◽  
Normal Controls

Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype–genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype–phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype–genotype correlations in congenital hypothyroidism.

Clinical and molecular genetic characterization of two patients with mutations in the phosphoglucomutase 1 (PGM1) gene

2018 ◽  
Vol 31 (7) ◽  
pp. 781-788 ◽  
Author(s):  
Yu Ding ◽  
Niu Li ◽  
Gouying Chang ◽  
Juan Li ◽  
Ruen Yao ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Chinese Han ◽  
Targeted Gene Sequencing ◽  
Molecular Genetic Characterization

Abstract Background The phosphoglucomutase 1 (PGM1) enzyme plays a central role in glucose homeostasis by catalyzing the inter-conversion of glucose 1-phosphate and glucose 6-phosphate. Recently, PGM1 deficiency has been recognized as a cause of the congenital disorders of glycosylation (CDGs). Methods Two Chinese Han pediatric patients with recurrent hypoglycemia, hepatopathy and growth retardation are described in this study. Targeted gene sequencing (TGS) was performed to screen for causal genetic variants in the genome of the patients and their parents to determine the genetic basis of the phenotype. Results DNA sequencing identified three variations of the PGM1 gene (NM_002633.2). Patient 1 had a novel homozygous mutation (c.119delT, p.Ile40Thrfs*28). In patient 2, we found a compound heterozygous mutation of c.1172G>T(p.Gly391Val) (novel) and c.1507C>T(p.Arg503*) (known pathogenic). Conclusions This report deepens our understanding of the clinical features of PGM1 mutation. The early molecular genetic analysis and multisystem assessment were here found to be essential to the diagnosis of PGM1-CDG and the provision of timely and proper treatment.

scholarly journals Novel Compound Heterozygous Pathogenic Mutations of SLC5A5 in a Chinese Patient With Congenital Hypothyroidism

2021 ◽  
Vol 12 ◽  
Author(s):  
Cao-Xu Zhang ◽  
Jun-Xiu Zhang ◽  
Liu Yang ◽  
Chang-Run Zhang ◽  
Feng Cheng ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Sodium Iodide ◽  
Chinese Patients ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Sodium Iodide Symporter ◽  
Transmembrane Segment ◽  
Pathogenic Mutations

Background and ObjectivesDefects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation.MethodsTwo hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro.ResultsIn 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired.ConclusionThe undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.

AGRN Gene Mutation Leads to Congenital Myasthenia Syndromes: A Pediatric Case Report and Literature Review

2020 ◽  
Vol 51 (05) ◽  
pp. 364-367
Author(s):  
Siyi Gan ◽  
Haiyan Yang ◽  
Ting Xiao ◽  
Zou Pan ◽  
Liwen Wu
Keyword(s):  
Gene Mutation ◽  
Muscle Weakness ◽  
Motor Development ◽  
Neuromuscular Junctions ◽  
Age Of Onset ◽  
Lower Limbs ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Congenital Myasthenia

AbstractThe congenital myasthenia syndromes (CMS) are a group of autosomal recessive or autosomal dominant diseases that affect neuromuscular junctions. CMS caused by AGRN mutations is very uncommon typically characterized by ptosis, mild weakness, and proximal limb weakness. We report the case of an 8-year-old female who exhibited the onset of motor development retardation from infancy and slow progression to proximal muscle weakness. Repeated nerve stimulation at 3 Hz showed a clear decrement with 17%. Whole exon sequencing showed an AGRN gene compound heterozygous mutation (c.5009C >T and c.5078T > C). She was treated with salbutamol but without improvement. Then pseudoephedrine was adapted as a treatment choice and obtained remarkable curative effect. We have summarized and analyzed 12 patients who have been reported in the literature. An early age of onset and muscle weakness in the lower limbs are the main feature of an early AGRN gene mutation. Both types of AGRN-related CMS respond favorably to ephedrine. This is the first report showing that pseudoephedrine is effective as a choice for the treatment of AGRN-related CMS.

scholarly journals A Novel Adrenocorticotropin Receptor Mutation Alters Its Structure and Function, Causing Familial Glucocorticoid Deficiency

2008 ◽  
Vol 93 (8) ◽  
pp. 3097-3105 ◽  
Author(s):  
Rocío A. Artigas ◽  
Angel Gonzalez ◽  
Erick Riquelme ◽  
Cristian A. Carvajal ◽  
Andreína Cattani ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Clinical Case ◽  
Stop Codon ◽  
Transmembrane Helix ◽  
Premature Stop Codon ◽  
Autosomal Recessive Disorder ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Dynamic Simulations ◽  
Glucocorticoid Deficiency

Abstract Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder characterized by unresponsiveness to ACTH. In this study, two mutations of the ACTH receptor (MC2R) gene are reported in this FGD clinical case. Objective: The objective of the study was to characterize a novel MC2R gene mutation in a compound heterozygous patient with FGD phenotype. Design: This was a clinical case description, biochemical, molecular, and bioinformatics analysis to describe a novel MC2R gene mutation. Patients: The subject of the study was a male diagnosed with primary adrenal insufficiency. The family history showed nonconsanguineous healthy parents, three healthy siblings, and one brother affected with FGD. Main Outcome Measures: The mutant MC2R-Ala126Ser showed significantly lower activity when it was stimulated with ACTH-(1–24) than did cells transfected with wild-type MC2R. Results: The molecular studies demonstrated the presence of an adenine heterozygous insertion (InsA1347) in the MC2R gene (G217fs) in the patient. This insertion was due to a frame shift mutation in one allele and a premature stop codon codifying an aberrant receptor of 247 residues (27.2 kDa). We also found a novel heterozygous mutation alanine 126 by serine. Molecular dynamic simulations showed that serine 126 side chain fluctuates forming a noncanonical intrahelical hydrogen bond in the transmembrane helix 3 of the mutated receptor. This produces a structural rearrangement of the MC2R internal cavities that may affect the ligand recognition and signal transduction throughout the G protein. Conclusions: We propose a molecular explanation for the reduced activity exhibited by the MC2R alanine 126 by serine mutant.

Mutation Screening of DUOX2 Gene in Children with Congenital Hypothyroidism

2020 ◽  
Author(s):  
Xiao-Yu Chen ◽  
Yong Liu ◽  
Jian-Hua Liu ◽  
Xiaosong Qin
Keyword(s):  
Congenital Hypothyroidism ◽  
Mutation Screening ◽  
Venous Blood ◽  
Chinese Patients ◽  
Dimensional Structure ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Gene Variants ◽  
The Relationship

Abstract Background: Congenital hypothyroidism(CH) is generally known as the most common neonatal endocrine disorder. However, the mutational spectrum of DUOX2 gene and the relationship between genotype and phenotype have not been fully established among Chinese CH patients. Therefore, The aim of this study was to screen DUOX2 mutations in Chinese patients with CH and to research the relationship between DUOX2 genotype and clinical phenotype.Methods: Eighty-six patients with CH were recruited from northeastern region of China. Peripheral venous blood samples were collected, genomic DNA was extracted , PCR and next-generation sequencing (NGS) were used to analyze all exons of DUOX2. Detailed medical data were collected, and the relationship between DUOX2 genotype and the clinical phenotype was preliminarily investigated.Results: NGS analysis of DUOX2 gene identified a total of 20 different gene variants in 26 patients(30.2%), which was consistent with the gene variants in Asian populations, among these variants 16 were known to be pathogenic or likely to be pathogenic, and four were suspected to be of uncertain significance. Three mutations (p.K530X, p.L1343F and p.R1110Q) were highly recurrent in our patient cohort. By using protein homology modeling method, the analysis of its three-dimensional structure suggested that the mutations p.336_337del and p.T1107fs caused the change of the protein.Conclusions: In our study, p.336_337del and p.T1107fs were found to be novel variants and p.K530X with the highest prevalence. Children with DUOX2 single allele heterozygous mutation or compound heterozygous mutation exhibited different morphological developments of the thyroid.

scholarly journals A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child

2020 ◽  
Vol 10 (01) ◽  
pp. e134-e136
Author(s):  
Nida Mirza ◽  
Smita Malhotra ◽  
Anupam Sibal
Keyword(s):  
Intrahepatic Cholestasis ◽  
Gall Stone ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Initial Symptom ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Presenting Symptoms ◽  
Abcb4 Gene ◽  
Type 3

AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.

scholarly journals Leptin Receptor Compound Heterozygosity in Humans and Animal Models

2021 ◽  
Vol 22 (9) ◽  
pp. 4475
Author(s):  
Claudia Berger ◽  
Nora Klöting
Keyword(s):  
Food Intake ◽  
Animal Models ◽  
Leptin Receptor ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Compound Heterozygosity ◽  
Therapy Options ◽  
Obese Phenotype ◽  
Deficient Mice

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.

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