Gcm2 Variant p.Y392S and Parathyroid Glands

Vaishali I Parekh, Lauren R Brinster, Bin Guan, William F Simonds, Lee S Weinstein, Sunita K Agarwal
Journal of the Endocrine Society, Volume 7, Issue 11, November 2023, bvad126
https://doi.org/10.1210/jendso/bvad126

Abstract

Context

The glial cells missing 2 (GCM2) gene functions as a transcription factor that is essential for parathyroid gland development, and variants in this gene have been associated with 2 parathyroid diseases: isolated hypoparathyroidism in patients with homozygous germline inactivating variants and primary hyperparathyroidism in patients with heterozygous germline activating variants. A recurrent germline activating missense variant of GCM2, p.Y394S, has been reported in patients with familial primary hyperparathyroidism.

Objective

To determine whether the GCM2 p.Y394S missense variant causes overactive and enlarged parathyroid glands in a mouse model.

Methods

CRISPR/Cas9 gene editing technology was used to generate a mouse model with the germline heterozygous Gcm2 variant p.Y392S that corresponds to the human GCM2 p.Y394S variant. Wild-type (Gcm2^+∕+) and germline heterozygous (Gcm2^+∕Y392S) mice were evaluated for serum biochemistry and parathyroid gland morphology.

Results

Gcm2^+∕Y392S mice did not show any change compared to Gcm2^+∕+ mice in serum calcium and parathyroid hormone levels, parathyroid gland histology, cell proliferation, or parathyroid gland size.

Conclusion

The mouse model of the p.Y392S variant of Gcm2 shows that this variant is tolerated in mice, as it does not increase parathyroid gland cell proliferation and circulating calcium or PTH levels. Further investigation of Gcm2^+∕Y392S mice to study the effect of this variant of Gcm2 on early events in parathyroid gland development will be of interest.

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