Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism

Date

2010-11

Authors

Morgan, Neil V.
Forman, Julia R.
Aycan, Zehra
Böber, Ece
Cesur, Yaşar
Kirby, Gail A.
Pasha, Shanaz S.
Çetinkaya, Semra Çağlar
Baş, Veysel Nihat
Demir, Korcan

Journal Title

Journal ISSN

Volume Title

Publisher

Wiley

Abstract

Objective Nonsyndromic 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 Because 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 Hundred and thirty-nine 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 six 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.

Description

Keywords

Thyrotropin-receptor, Molecular-cloning, Resistance, Expression, Identification, Environment, Rhodopsin, Hormone, Complex, Endocrinology & metabolism

Citation

Cangül, H. vd. (2010). "Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism". Clinical Endocrinology, 73(5), 671-677.