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

Hakan Cangul (1) , Neil V Morgan (1) , Julia R Forman (2) , Halil Saglam (3) , Zehra Aycan (4) , Tahsin Yakut (5) , Tuna Gulten (5) , Omer Tarim (3) , Ece Bober (6) , Yasar Cesur (7) , Gail A Kirby (1) , Shanaz Pasha (1) , Mutlu Karkucak (5) , Erdal Eren (3) , Veysel Bas (4) , Korcan Demir (6)

1 Medical & Molecular Genetics
2 ABI - Atelier de BioInformatique
3 Department of Paediatric Endocrinology
4 Division of Paediatric Endocrinology
5 Department of Medical Genetics
6 Department of Paediatrics, Division of Endocrinology
7 Departments of Pediatric Endocrinology

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.

Mots clés: Medicine

Hakan Cangul, Neil V Morgan, Julia R Forman, Halil Saglam, Zehra Aycan, et al.. Novel TSHR mutations in consanguineous families with congenital non-goitrous hypothyroidism. Clinical Endocrinology, 2010, 73 (5), pp.671. ⟨10.1111/j.1365-2265.2010.03849.x⟩. ⟨hal-00583581⟩