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 function. First evidence for the role of TSH receptor defects in the pathogenesis of congenital thyroid disorders was elucidated by the presence of activating germline mutations leading to congenital hyperthyroidism. After the finding of partial loss-of-function mutations leading to hyperthyrotropinemia it was speculated that a more severe phenotype with hypothyroidism and hypoplasia of the gland (thyroid dysgenesis) would be the result, if complete loss-of-function mutations like the isoleucine167 to asparagine mutation would occur in a homozygote or compound heterozygote state. The screening of TSHR gene mutations by SSCP in a well de fined cohort of 100 children with congenital hypothyroidism (CH), diagnosed and followed since 1978 in the Childrens Hospital of Berlin, revealed one patient with hypoplasia of the thyroid to be positive for two compound heterozygote inactivating mutations of the TSHR gene, indicating thereby that the clinical approach to define phenotypes of interest could be helpful to understand the fundamental process of thyroid development.