Frequency and Clinical Implication of the R450H Mutation in the Thyrotropin Receptor Gene in the Japanese Population Detected by Smart Amplification Process 2

Abstract

In Japanese pediatric patients with thyrotropin (TSH) resistance, the R450H mutation in TSH receptor gene (TSHR) is occasionally observed. We studied the frequency and clinical implication of the R450H mutation in TSHR in the general population of Japanese adults using smart amplification process 2 (SmartAmp2). We designed SmartAmp2 primer sets to detect this mutation using a drop of whole blood. We analyzed thyroid function, antithyroid antibodies, and this mutation in 429 Japanese participants who had not been found to have thyroid disease. Two cases without antithyroid antibodies were heterozygous for the R450H mutation in TSHR. Thus, the prevalence of this mutation was 0.47% in the general population and 0.63% among those without antithyroid antibodies. Their serum TSH concentrations were higher than the average TSH concentration not only in subjects without antithyroid antibodies but also in those with antithyroid antibodies. The R450H mutation in TSHR is relatively common in the Japanese population and potentially affects thyroid function. The present study demonstrates that the SmartAmp2 method is useful to detect the R450H mutation in TSHR, which is one of the common causes of TSH resistance in the Japanese population.

Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism

“…Nucleotide sequencing of patient A (I-1) revealed to have a homozygous SNP in the DIO2 gene (c.274 A > G, DIO2 T92A), which had previously been identified in a certain portion of population as significant SNP 14 , 15 and a heterozygous mutation in TSHR gene (c.1349 G > A, R450H) 8 , 16 – 18 (data not shown). Interestingly, patients B also had a homozygous DIO2 T92A together with heterozygous TSHR F525S (data not shown).…”

“…Patients II-1, II-4, and II-5 in family A who have heterozygous R450H had mild subclinical hypothyroidism and patient III-1 who had a homozygous TSHR R450H mutation had severe congenital hypothyroidism. The prevalence of TSHR R450H mutation is reported as 0.47% in the general Japanease population 18 and the prevalence of biallelic TSHR mutations was estimated to 4.3% in Japanese patients with moderate to severe congenital hypothyroidism 8 . Patient A (I-1) having heterozygous TSHR R450H and homozygous DIO2 T92A showed evident decreased DIO2 activity, but III-1 having homozygous TSHR R450H and heterozygous DIO2 T92A did not show decreased DIO2 activity.…”

Pathogenic <i>TSHR</i> variants in children with thyroid dysgenesis

“…Все выявленные нами варианты у пробандов 4 и 5 представляют собой мутации с потерей функции (LOF-варианты) [ 7 ]. У 2 детей выявлен вариант p.R450H, который наиболее распространен в Азии [ 32 ][ 33 ]. Мама пациентки N1 по национальности азербайджанка, мама ребенка N3 — киргизка.…”

Resistance to thyrotropin

“…In various East-Asian cohorts with nonsyndromic congenital hyperthyrotropinemia (hypothyroidism), between 4.2% and 9.4% harbored mono- or biallelic TSHR mutations. About 75% of which were of the R450H variant that is found at a prevalence of about 0.5% in the corresponding general populations [33, 34, 46, 49]. TSHR LOF mutations are the most common cause of non-goitrous CH in consanguineous families [28] and specific founder mutations have been found in over half of patients with subclinical hypothyroidism in a consanguineous Arab-Muslim population [31].…”