Loss-of-function mutations in the thyrotropin receptor gene as a major determinant of hyperthyrotropinemia in a consanguineous community.
BACKGROUND
Resistance to TSH (RTSH) is a condition of impaired responsiveness of the thyroid gland to TSH, characterized by elevated serum TSH, low or normal thyroid hormone levels, and hypoplastic or normal-sized thyroid gland.


OBJECTIVE
The aim of the study was to evaluate the clinical course and the genotype-phenotype relationship of RTSH caused by two different TSH receptor (TSHR) gene mutations in a consanguineous population.


METHODS
We conducted a clinical and genetic investigation of 46 members of an extended family and 163 individuals living in the same town. In vitro functional studies of the mutant TSHRs were also performed.


RESULTS
Two TSHR gene mutations (P68S and L653V) were identified in 33 subjects occurring as homozygous L653V (five subjects), heterozygous L653V (20 subjects), heterozygous P68S (four subjects), and compound heterozygous L653V/P68S (four subjects). With the exception of one individual with concomitant autoimmune thyroid disease, all homozygotes and compound heterozygotes presented with compensated RTSH (high TSH with free T(4) and T(3) in the normal range). Only nine of 24 heterozygotes had mild hyperthyrotropinemia. The L653V mutation resulted in a higher serum TSH concentration and showed a more severe in vitro abnormality than P68S. Haplotype analysis predicted a founder of the L653V six to seven generations earlier, whereas the P68S is older. Cross-sectional and prospective longitudinal studies indicate that TSH and T(4) concentrations remain stable over time.


CONCLUSIONS
High frequency hyperthyrotropinemia in an Israeli Arab-Muslim consanguineous community is attributed to two inactivating TSHR gene mutations. Concordant genotype-phenotype was demonstrated clinically and by in vitro functional analysis. Retrospective and prospective studies indicate that in the absence of concomitant autoimmune thyroid disease, elevated TSH levels reflect stable compensated RTSH.
Tenenbaum-Rakover
Yardena
Y
Pediatric Endocrine Unit, Ha'Emek Medical Center, and Technion Faculty of Medicine, 31096 Haifa, Israel. rakover_y@clalit.org.il
Grasberger
Helmut
H
Mamanasiri
Sunee
S
Ringkananont
Usanee
U
Montanelli
Lucia
L
Barkoff
Marla S
MS
Dahood
Ahmad Mahameed-Hag
AM
Refetoff
Samuel
S
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000818:Animals; D018912:Arabs; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology*; D010375:Pedigree; D010641:Phenotype; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013960:Thyroid Function Tests; D013972:Thyrotropin / Q000097:blood*; D055815:Young Adult
D011989:Receptors, Thyrotropin; D013972:Thyrotropin