title: A novel activating mutation in transmembrane helix 6 of the thyrotropin receptor as cause of hereditary nonautoimmune hyperthyroidism.
abstract: Constitutively-activating germline mutations of the thyrotropin receptor (TSHR) gene are very rare and are considered the cause of hereditary nonautoimmune hyperthyroidism. We describe four affected individuals from a Caucasian family: a mother and her three children, and an unaffected father. The mother and her first two children presented in a similar manner: lifelong histories of heat intolerance, hyperactivity, fast heart rate, reduced energy, increased appetite, and scrawny build. They all developed goiter in childhood and showed a suppressed TSH and elevated thyroxine (T(4)). The last child, a 12-year-old female, presented with no clinical symptoms or palpable neck mass, but with a suppressed TSH, elevated T(4) and thyromegaly detected by ultrasound. Mutation analysis of the TSHR gene in all family members revealed a novel heterozygous germline mutation resulting in the substitution of phenylalanine (TTC) by serine (TCC) at codon 631 in transmembrane helix 6 in the mother and all three children. Functional characterization of this germline mutation showed constitutive activation of the G(s)-mediated cyclic adenosine monophosphate (cAMP) pathway, which controls thyroid hormone production and thyroid growth. Molecular characterization of F631S demonstrates that this activating mutation plays a key role in the development of hereditary hyperthyroidism in this family although the timing of onset of clinical manifestations in the subjects may depend on other, as yet unidentified, factors.
authors.affiliation: University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Benjamin U
authors.initials: BU
authors.lastname: Nwosu
authors.forename: Loukas
authors.initials: L
authors.lastname: Gourgiotis
authors.forename: Marvin C
authors.initials: MC
authors.lastname: Gershengorn
authors.forename: Susanne
authors.initials: S
authors.lastname: Neumann
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D011989:Receptors, Thyrotropin / Q000235:genetics*
chemical_list: D011989:Receptors, Thyrotropin; D000242:Cyclic AMP