TSHB R75G is a founder variant and prevalent cause of low or undetectable TSH in Indian Jews

Author:

Shaki David12,Eskin-Schwartz Marina3,Hadar Noam3,Bosin Emily4,Carmon Lior12,Refetoff Samuel5,Hershkovitz Eli12,Birk Ohad S3,Haim Alon12

Affiliation:

1. 1Pediatric Endocrinology Unit, Saban Pediatric Medical Center for Israel, Beer Sheva, Israel

2. 2Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

3. 3Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel

4. 4Endocrinology Lab, Soroka University Medical Center, Beer Sheva, Israel

5. 5Departments of Medicine and Pediatrics and the Committee on Genetics, The University of Chicago, Chicago, Illinois, USA

Abstract

Objective Bi-allelic loss-of-function mutations in TSHB, encoding the beta subunit of thyroid-stimulating hormone (TSH), cause congenital hypothyroidism. Homozygosity for the TSHB p.R75G variant, previously described in South Asian individuals, does not alter TSH function but abrogates its detection by some immune detection-based platforms, leading to erroneous diagnosis of hyperthyroidism. We set out to identify and determine the carrier rate of the p.R75G variant among clinically euthyroid Bene Israel Indian Jews, to examine the possible founder origin of this variant worldwide, and to determine the phenotypic effects of its heterozygosity. Design Molecular genetic studies of Bene Israel Jews and comparative studies with South Asian cohort. Methods TSHB p.R75G variant tested by Sanger sequencing and restriction fragment length polymorphism (RFLP). Haplotype analysis in the vicinity of the TSHB gene performed using SNP arrays. Results Clinically euthyroid individuals with low or undetectable TSH levels from three apparently unrelated Israeli Jewish families of Bene Israel ethnicity, originating from the Mumbai region of India, were found heterozygous or homozygous for the p.R75G TSHB variant. Extremely high carrier rate of p.R75G TSHB in Bene Israel Indian Jews (~4%) was observed. A haplotype block of 239.7 kB in the vicinity of TSHB shared by Bene Israel and individuals of South Asian origin was detected. Conclusions Our findings highlight the high prevalence of the R75G TSHB variant in euthyroid Bene Israel Indian Jews, demonstrate that heterozygosity of this variant can cause erroneous detection of subnormal TSH levels, and show that R75G TSHB is an ancient founder variant, delineating shared ancestry of its carriers.

Publisher

Bioscientifica

Subject

Endocrinology, Diabetes and Metabolism

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Approach to the Patient With Raised Thyroid Hormones and Nonsuppressed TSH;The Journal of Clinical Endocrinology & Metabolism;2023-11-21

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