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| Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism |
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| Author(s): Biebermann H, Schoneberg T, Krude H, Schultz G, Gudermann T, Gruters A |
| Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Volume: 82 Issue: 10 Pages: 3471-3480 Published: OCT 1997 |
| Times Cited: 103 References: 45 |
| Abstract: The pathogenesis of congenital hypothyroidism due to thyroid dysgenesis is still unknown. A point mutation in the TSH receptor (TSHR) of the hypothyroid hyt/hyt mouse invoked the TSHR as a candidate gene for congenital hypothyroidism. Therefore, we screened for mutations in the TSHR gene in patients with congenital hypothyroidism and hypoplasia of the gland. In one girl detected in neonatal screening with the confirmed diagnosis of permanent congenital hypothyroidism with reduced thyroid volume, two novel mutations in the TSHR gene were identified. Single strand conformational polymorphism and subsequent DNA sequencing studies of a fragment of the TSHR gene showed that the patient is a compound heterozygote for 2 loss of function mutations in exon 10 of the TSHR gene. In the mutant maternal allele, 18 nucleotides (positions 1217-1234) are deleted, and 4 novel bp are inserted, resulting in a frameshift and premature termination of the coding sequence. Transfection studies showed that this truncated TSHR was trapped intracellularly and completely lacked cell surface expression. The paternal gene harbors a missense mutation at nucleotide position 1170, leading to the exchange of the highly conserved C-390 for a W residue. This alteration resulted in a drastic loss of affinity and potency of TSH acting at the mutant compared to the wild-type receptor. In contrast to the published loss of function mutations of the TSHR leading to euthyroid hyperthyrotropinemia, the two new mutations lead to persistent congenital hypothyroidism and defective organ development. Further studies will have to analyze to what extent TSHR mutations are involved in the pathogenesis of congenital hypothyroidism as opposed to other genetic or environmental factors. |
| Document Type: Article |
| Language: English |
Addresses:
1. HUMBOLDT UNIV BERLIN, KLINIKUM RUDOLF VIRCHOW, FAK MED, KLIN & POLIKLIN KINDERHEILKUNDE, D-13353 BERLIN, GERMANY
2. FREE UNIV BERLIN, KLINIKUM BENJAMIN FRANKLIN, INST PHARMAKOL, D-12200 BERLIN, GERMANY |
| Publisher: ENDOCRINE SOC, 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA |
| Subject Category: Endocrinology & Metabolism |
| IDS Number: YA002 |
| ISSN: 0021-972X |
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