Novel TSHR mutations in consanguineous families with congenital non-goitrous hypothyroidism

• Published in: Clinical Endocrinology
• Language: English
• Published: Wiley-Blackwell 2011
• Subjects: Medicine; Pasteur; Erdal; sami
• Online Access: http://hdl.handle.net/2262/54572; https://doi.org/10.1111/j.1365-2265.2010.03849.x

Abstract Objective: Non-syndromic autosomal recessively inherited non-goitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB, and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG. Design: Since consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families.Patients: 139 children with CHNG phenotype born to consanguineous families.Measurements: First we investigated cases for evidence of linkage to the four known-CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation specific disease phenotype. Results: Homozygous germline TSHR mutations were detected in 6 families (5%), but no mutations were detected in PAX8, TSHB, and NKX2-5. Four of TSHR mutations had not previously been described. Genotype-phenotype correlations were established and found to be related to the predicted structural effects of the mutations.Conclusions: Known-causative genes account for the development of CHNG only in a minority of cases and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG. : 14 Jun 2007 account with Record No. 1246442 merged into this account by Ms. Norma SweeneyComments from Account 1246442: 12 Apr 2007 account with Record No. 1565756 merged into this account by Ms. Francesca Gibson14 Jan 2005 account with Record No. 1252346 merged into this account by Mr. Daniel Mills14 Jan 2005 account with Record No. 1249814 merged into this account by Mr. Daniel MillsComments from Account 1249814: Comments from Account 1252346: Comments from Account 1565756: (Aycan, Zehra) [e-mail] (Cangul, Hakan) [e-mail] (Morgan, Neil V) [e-mail] (Forman, Julia R) [e-mail] (Saglam, Halil) [e-mail] (Aycan, Zehra) [e-mail] (Yakut, Tahsin) [e-mail] (Gulten, Tuna) [e-mail] (Tarim, Omer) [e-mail] (Bober, Ece) [e-mail] (CESUR, Yasar) [e-mail] (Kirby, Gail A) [e-mail] (Pasha, Shanaz) [e-mail] (Karkucak, Mutlu) [e-mail] (Eren, Erdal) [e-mail] (Bas, Veysel) [e-mail] (Demir, Korcan) University of Birmingham, School of Clinical and Experimental Medicine, Medical & Molecular Genetics - Birmingham - UNITED KINGDOM (Cangul, Hakan) University of Birmingham, School of Clinical and Experimental Medicine, Medical & Molecular Genetics - Birmingham - UNITED KINGDOM (Morgan, Neil V) Institut Pasteur, Structural Bioinformatics Unit - Paris - FRANCE (Forman, Julia R) Uludag University School of Medicine, Department of Paediatric Endocrinology - Bursa - TURKEY (Saglam, Halil) Dr Sami Ulus Woman Health, Children Research Hospital, Division of Paediatric Endocrinology - Ankara - TURKEY (Aycan, Zehra) Uludag University School of Medicine, Department of Medical Genetics - Bursa - TURKEY (Yakut, Tahsin) Uludag University School of Medicine, Department of Medical Genetics - Bursa - TURKEY (Gulten, Tuna) Uludag University School of Medicine, Department of Paediatric Endocrinology - Bursa - TURKEY (Tarim, Omer) Dokuz Eylul University, Faculty of Medicine, Department of Paediatrics, Division of Endocrinology - Izmir - TURKEY (Bober, Ece) Faculty of Medicine ,Yuzuncu Y?l University, Departments of Pediatric Endocrinology - Van - TURKEY (CESUR, Yasar) University of Birmingham, School of Clinical and Experimental Medicine, Medical & Molecular Genetics - Birmingham - UNITED KINGDOM (Kirby, Gail A) University of Birmingham, School of Clinical and Experimental Medicine, Medical & Molecular Genetics - Birmingham - UNITED KINGDOM (Pasha, Shanaz) Uludag University School of Medicine, Department of Medical Genetics - Bursa - TURKEY (Karkucak, Mutlu) Uludag University School of Medicine, Department of Paediatric Endocrinology - Bursa - TURKEY (Eren, Erdal) Dr Sami Ulus Woman Health, Children Research Hospital, Division of Paediatric Endocrinology - Ankara - TURKEY (Bas, Veysel) Dokuz Eylul University, Faculty of Medicine, Department of Paediatrics, Division of Endocrinology - Izmir - TURKEY (Demir, Korcan) FRANCE TURKEY UNITED KINGDOM