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.

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.

Novel Sodium/Iodide Symporter Compound Heterozygous Pathogenic Variants Causing Dyshormonogenic Congenital Hypothyroidism

Thyroid ◽  
2019 ◽  
Vol 29 (7) ◽  
pp. 1023-1026 ◽  
Author(s):  
Mariano Martín ◽  
Carlos Eduardo Bernal Barquero ◽  
Romina Celeste Geysels ◽  
Patricia Papendieck ◽  
Victoria Peyret ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Sodium Iodide ◽  
Compound Heterozygous ◽  
Sodium Iodide Symporter ◽  
Pathogenic Variants

scholarly journals A Novel Compound Heterozygous Mutation of FSHR Causes Primary Ovarian Insufficiency

2020 ◽  
Author(s):  
Nan Zhang ◽  
Jiawei Xu ◽  
Xiao Bao ◽  
Feifei Zhao ◽  
Dayuan Shi ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Primary Ovarian Insufficiency ◽  
Compound Heterozygous Mutation ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Primary Amenorrhea ◽  
Compound Heterozygous ◽  
Ovarian Insufficiency ◽  
Functional Analyses

Abstract Background: Primary ovarian insufficiency, one of the main causes of female infertility, is a heterogeneous disease when it comes to the phenotype and etiology. Familial cases are observed in approximately 10% of patients which indicates a strong genetic component. However, the underlying cause remains to be identified in most cases of patients.Methods: Here we studied an un-consanguineous Han Chinese family in which four siblings are primary amenorrhea and hypergonadotropic hypogonadism. Three siblings with POI and one unaffected sibling were exome sequenced. Also, other members in this family were genotyped by Sanger Sequencing. In silicon and in-vitro functional analyses were performed.Results: Whole exome sequencing identified a shared novel compound heterozygous mutation of FSHR gene in all the affected members. c.1412T>G, the first variant identified in FSHR IL2(intracellular loop2) in POI patients, and another novel mutation c.1090_1091del were the genetic etiology of this family. In-vitro functional analyses showed that cAMP (second messenger of FSHR) producing was abolished by c.1412T>G. Conclusions: Our study identified two novel FSHR mutations in a compound heterozygous state and gave the evidence that the FSHR IL2 could play a crucial role in FSHR-caused POI.

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.

scholarly journals Two Novel Mutations in the Gonadotropin-Releasing Hormone Receptor Gene in Brazilian Patients with Hypogonadotropic Hypogonadism and Normal Olfaction1

2001 ◽  
Vol 86 (6) ◽  
pp. 2680-2686 ◽  
Author(s):  
E. M. F. Costa ◽  
G. Y. Bedecarrats ◽  
B. B. Mendonca ◽  
I. J. P. Arnhold ◽  
U. B. Kaiser ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Hypogonadotropic Hypogonadism ◽  
Gnrh Receptor ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Intracellular Loop ◽  
Amino Terminal ◽  
Inactivating Mutations

Several point mutations in the GnRH receptor gene have been described in an autosomal recessive form of congenital isolated hypogonadotropic hypogonadism (HH). We investigated 17 Brazilian patients (10 males and 7 females) from 14 different families, with HH and normal olfaction. The diagnosis of HH was based on absent or incomplete sexual development after 17 yr of age associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. The coding region of the GnRH receptor gene was amplified by PCR and directly sequenced. A novel missense mutation, Arg139His, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified in the homozygous state in one female with complete HH. The Arg139His mutation completely eliminated detectable GnRH-binding activity and prevented GnRH-induced stimulation of inositol phosphate accumulation in vitro. In another family, a new compound heterozygous mutation (Asn10Lys and Gln106Arg) was identified in four siblings (two males and two females) with partial HH. The Gln106Arg mutation, located in the first extracellular loop, has been previously described, and in vitro analysis indicated that the mutant receptor was able to bind GnRH, but with a reduced affinity. The Asn10Lys mutation in the extracellular amino-terminal domain of the receptor also reduced the affinity for GnRH in vitro. In this family we also identified a previously described silent polymorphism at amino acid residue 151 in the second intracellular loop that segregated with the two inactivating mutations of the GnRH receptor. This polymorphism was also found in two unrelated patients with sporadic HH without GnRH receptor loss of function mutations. No mutations were identified in the remaining cases. A good correlation between genotype and phenotype was found in our patients. The woman, who is homozygous for the completely inactivating Arg139His mutation, has complete HH with undetectable serum basal LH and FSH levels that failed to respond to GnRH stimulation. In addition, the affected patients who are compound heterozygotes for the Asn10Lys/Gln106Arg mutations, have partial HH with low serum basal LH levels that were responsive to GnRH stimulation. No clinical or hormonal differences were found between HH patients with and without mutations in the GnRH receptor gene, indicating that these data do not contribute to the identification of HH patients with GnRH receptor mutations. In conclusion, we report the first naturally occurring mutation within the conserved DRS motif of the GnRH receptor in a female with complete HH and a novel compound heterozygous mutation (Asn10Lys and Gln106Arg) in a family with partial HH, increasing the repertoire of the inactivating mutations of the GnRH receptor.

Novel Mutations of Cathepsin C Gene in Two Chinese Patients with Papillon-Lefèvre Syndrome

2007 ◽  
Vol 86 (8) ◽  
pp. 735-738 ◽  
Author(s):  
Y. Yang ◽  
X. Bai ◽  
H. Liu ◽  
L. Li ◽  
C. Cao ◽  
...  
Keyword(s):  
Tooth Loss ◽  
Case Reports ◽  
Mutation Screening ◽  
Chinese Patients ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Cathepsin C ◽  
Lysosomal Protease ◽  
Palmoplantar Hyperkeratosis

Papillon-Lefèvre syndrome (PLS) is an inherited human disease characterized by early-onset periodontitis and palmoplantar hyperkeratosis. Mutations of the lysosomal protease cathepsin C ( CTSC) gene have been shown to be the genetic cause of Papillon-Lefèvre syndrome. There are several case reports in China, while there has been no study on the genetic analysis of PLS. We studied two Chinese patients carrying Papillon-Lefèvre syndrome and showing premature tooth loss and palmoplantar hyperkeratosis. Mutation screening and sequence analysis of the CTSC gene revealed a compound heterozygous mutation (c.415 G>A and c.778 T>C) in one patient, and two novel compound heterozygous mutations (c.851G>A and c.112delCCTG) in the other patient. Our novel discovery indicates that the phenotypes observed in these two patients are due to the CTSC gene mutation.

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.

Sign in / Sign up

Export Citation Format

Share Document