Department of Pediatrics, Division of Endocrinology
Medical Subject Headings
Adolescent; Base Sequence; Cell Line; Cyclic AMP; DNA Mutational Analysis; Family Health; Female; *Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Hyperthyroidism; Male; Molecular Sequence Data; *Mutation; Protein Structure, Tertiary; Receptors, Thyrotropin
Endocrinology, Diabetes, and Metabolism | Pediatrics
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.
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Citation: Benjamin U. Nwosu, Loukas Gourgiotis, Marvin C. Gershengorn and Susanne Neumann. Thyroid. May 2006, 16(5): 505-512. doi:10.1089/thy.2006.16.505. Link to article on publisher's site
Nwosu, Benjamin U.; Gourgiotis, Loukas; Gershengorn, Marvin C.; and Neumann, Susanne, "A novel activating mutation in transmembrane helix 6 of the thyrotropin receptor as cause of hereditary nonautoimmune hyperthyroidism" (2006). Pediatric Publications and Presentations. Paper 4.