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Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
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Objective
Loss of function mutations in the insulin receptor substrate 4 (IRS4) gene cause a rare form of X-linked congenital central hypothyroidism in boys and men. Affected individuals show decreased thyroid-stimulating hormone (TSH) secretion. Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and downstream effectors. How loss of IRS4 affects TSH synthesis or secretion is unresolved. We therefore assessed IRS4’s role in the hypothalamic–pituitary–thyroid axis of Irs4 knockout mice.
Methods
We generated two global Irs4 knockout mouse lines harboring either two or four base-pair deletions that result in frameshifts and loss of most of the IRS4 protein.
Results
Under normal laboratory conditions, Irs4 knockout males did not exhibit impairments in pituitary expression of TSH subunit genes (Tshb or Cga) or in the thyrotropin-releasing hormone (TRH) receptor. Additionally, their serum thyroid hormone, triiodothyronine (T3) and thyroxine (T4), and hypothalamic Trh expression levels were normal. When Irs4 knockouts were rendered hypothyroid with a low-iodine diet supplemented with propylthiouracil for 3 weeks, their serum TSH increased similarly to wild-type males.
Conclusion
Overall, Irs4 knockout mice do not exhibit central hypothyroidism or otherwise appear to phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these animals.
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
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Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
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Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
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Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
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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.
