A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism

Cangül, Hakan; Aycan, Zehra; Kendall, Michaela; Baş, Veysel Nijat; Saglam, Yaman; Barrett, Timothy

doi:10.1515/jpem-2013-0314

Cited by 15 publications

(18 citation statements)

References 6 publications

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“…In contrast, a previous report of Turkish patients with homozygous p.R434X showed mental retardation due to delayed diagnosis at 6 months of age (26). Therefore, early diagnosis by neonatal screening programs and early treatment are important for patients with DUOX2 defects, even for transient CH.…”

Section: Discussionmentioning

confidence: 74%

“…Other reports have shown that biallelic DUOX2 mutations cause mild to moderate CH (13,14,15,16,19,22,30). Recently, some studies have shown that DUOX2 defects are the predominant cause of CH associated with dyshormonogenesis (13,14,15,16,25,26).…”

Section: Discussionmentioning

confidence: 99%

“…(10,13,19). The locations of all DUOX2 mutations reported to date (8,13,14,15,16,19,20,21,22,23,24,25,26,27,28) For most patients, the L-thyroxine dose could be reduced by about 2-4 years of age, except for the twins in cases 10, 11 and 21. Twenty-one of the 24 patients were able to receive reduced doses of L-thyroxine.…”

Section: Clinical Course Of Patients With Biallelic Mutations In Duox2mentioning

confidence: 99%

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Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Maruo

Nagasaki

Matsui

et al. 2016

European Journal of Endocrinology

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Aim: We previously reported that biallelic mutations in dual oxidase 2 (DUOX2) cause transient hypothyroidism.Since then, many cases with DUOX2 mutations have been reported. However, the clinical features and prognosis of individuals with DUOX2 defects have not been clarified. Objective: We investigated the prognosis of patients with congenital hypothyroidism (CH) due to DUOX2 mutations. Patients: Twenty-five patients were identified by a neonatal screening program and included seven familial cases. Their serum TSH values ranged from 18.9 to 734.6 mU/l. Twenty-two of the patients had low serum free thyroxine (fT 4 ) levels (0.17-1.1 ng/dl). Twenty-four of the patients were treated with L-thyroxine. Methods: We analyzed the DUOX2, thyroid peroxidase, Na C /I K symporter, and dual oxidase maturation factor 2 genes of these 25 patients by PCR-amplified direct sequencing. An additional 11 genes were analyzed in 11 of the 25 patients using next-generation sequencing. Results: All patients had biallelic DUOX2 mutations, and seven novel alleles were detected. Fourteen of the patients were able to discontinue replacement therapy, and seven were receiving reduced L-thyroxine doses. Normalization of thyroglobulin lagged several years behind the completion of treatment. Two patients showed permanent hypothyroidism. Except for one case of a learning disability, growth and psychomotor development were normal. Conclusion: The prognosis of Japanese patients with DUOX2 defects was usually transient CH. Delayed improvement of thyroglobulin indicates that these patients have subclinical hypothyroidism. Hypothyroidism did not recur in patients during the study period (up to 18 years old).

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Course Of Patients With Biallelic Mutations In Duox2mentioning

confidence: 99%

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Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Maruo

Nagasaki

Matsui

et al. 2016

European Journal of Endocrinology

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“…Further comprehensive functional assessments of the detected mutation will reveal its exact mechanism in the pathogenesis of CH. The R434X mutation in the DUOXA2 was detected by a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes, suggesting a new testing strategy which uses next-generation sequencing in CH cases (14). …”

Section: Discussionmentioning

confidence: 99%

A Novel c.554+5C>T Mutation in the DUOXA2 Gene Combined with p.R885Q Mutation in the DUOX2 Gene Causing Congenital Hypothyroidism

Zheng¹,

Shao

Qiu³

et al. 2016

Jcrpe

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The coexistence of mutations in the dual oxidase maturation factor 2 (DUOXA2) and dual oxidase 2 (DUOX2) genes is rarely identified in congenital hypothyroidism (CH). This study reports a boy with CH due to a novel splice-site mutation in the DUOXA2 gene and a missense mutation in the DUOX2 gene. A four-year-old boy was diagnosed with CH at neonatal screening and was enrolled in this study. The DUOXA2, DUOX2, thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) genes were considered for genetic defects screening. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen the mutations in the exon fragments. Family members of the patient and the controls were also enrolled and evaluated. The boy harbored compound heterozygous mutations including a novel splice-site mutation c.554+5C>T in the maternal DUOXA2 allele and c.2654G>A (p.R885Q) in the paternal DUOX2 allele. The germline mutations from his parents were consistent with an autosomal recessive inheritance pattern. No mutations in the TPO and TSHR genes were detected. A novel splice-site mutation c.554+5C>T in the DUOXA2 gene and a mutation p.R885Q in the DUOX2 gene were identified in a 4-year-old patient with goitrous CH.

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“…To investigate genetic background of CH, we developed a two-tier strategy combining genetic linkage studies and full sequencing of candidate genes in familial cases and identified several mutations to date in different CH genes. [16][17][18][19][20][21][22][23][24][25][26] In the current study we aimed to determine genetic cause of CH in a consanguineous family with three affected siblings. Here we report a homozygous duplication (c.1184_1187dup4) in the TPO gene detected in all cases and associated clinical phenotypes.…”

Section: Introductionmentioning

confidence: 99%

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family

2015

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Congenital hypothyroidism (CH) is the most common neonatal endocrine disease, and germ-line mutations in the TPO gene cause the inherited form of the disease. Our aim in this study was to determine the genetic basis of congenital hypothyroidism in three affected children coming from a consanguineous Turkish family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First, we investigated the potential genetic linkage of the family to any known CH locus, using microsatellite markers, and then screened for mutations in linked-gene by conventional sequencing. The family showed potential linkage to the TPO gene and we detected a homozygous duplication (c.1184_1187dup4) in all cases. The mutation segregated with disease status in the family. This study confirms the pathogenicity of the c.1184_1187dup4 mutation in the TPO gene and helps establish a genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.

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A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism

Cited by 15 publications

References 6 publications

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty

A Novel c.554+5C>T Mutation in the DUOXA2 Gene Combined with p.R885Q Mutation in the DUOX2 Gene Causing Congenital Hypothyroidism

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family

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