THE GENE FOR THE THYROTROPIN RECEPTOR (TSHR) AS A CANDIDATE GENE FOR CONGENITAL HYPOTHYROIDISM WITH THYROID DYSGENESIS

According to the central role of the TSH receptor for thyroid function and growth the gene for the TSH receptor is a possible candidate gene for mutations which result in an impairment of thyroid growth and fun ction (Vassart and Dumont 1992). First evidence for the role of TSH re ceptor defects in the pathogenesis of congenital thyroid disorders was elucidated by the presence of activating germline mutations leading t o congenital hyperthyroidism (Duprez et al., 1994). After the finding of partial loss-of-function mutations leading to hyperthyrotropinemia (Sunthornthepvarakul et al., 1995) it was speculated that a more sever e phenotype with hypothyroidism and hypoplasia of the gland (thyroid d ysgenesis) would be the result, if complete loss-of-function mutations like the isoleucine 167 to asparagine mutation would occur in a homoz ygote or compound heterozygote state. The screening of TSHR gene mutat ions by SSCP in a well defined cohort of 100 children with congenital hypothyroidism (CH), diagnosed and followed since 1978 in the Children s Hospital of Berlin, revealed one patient with hypoplasia of the thyr oid to be positive for two compound heterozygote inactivating mutation s of the TSHR gene, indicating thereby that the clinical approach to d efine phenotypes of interest could be helpful to understand the fundam ental process of thyroid development.