Parekh Vaishali I, Brinster Lauren R, Guan Bin, Simonds William F, Weinstein Lee S, Agarwal Sunita K
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Office of Research Services, Division of Veterinary Resources, National Institutes of Health, Bethesda, MD 20892, USA.
J Endocr Soc. 2023 Oct 6;7(11):bvad126. doi: 10.1210/jendso/bvad126. eCollection 2023 Oct 9.
The glial cells missing 2 () 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 , p.Y394S, has been reported in patients with familial primary hyperparathyroidism.
To determine whether the p.Y394S missense variant causes overactive and enlarged parathyroid glands in a mouse model.
CRISPR/Cas9 gene editing technology was used to generate a mouse model with the germline heterozygous variant p.Y392S that corresponds to the human p.Y394S variant. Wild-type () and germline heterozygous () mice were evaluated for serum biochemistry and parathyroid gland morphology.
mice did not show any change compared to mice in serum calcium and parathyroid hormone levels, parathyroid gland histology, cell proliferation, or parathyroid gland size.
The mouse model of the p.Y392S variant of 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 mice to study the effect of this variant of on early events in parathyroid gland development will be of interest.
胶质细胞缺失2（GCM2）基因作为一种转录因子，对甲状旁腺发育至关重要，该基因的变异与两种甲状旁腺疾病相关：纯合子种系失活变异患者的孤立性甲状旁腺功能减退症，以及杂合子种系激活变异患者的原发性甲状旁腺功能亢进症。在家族性原发性甲状旁腺功能亢进症患者中已报道了一种复发性种系激活错义变异，即p.Y394S。
确定GCM2基因的p.Y394S错义变异是否会导致小鼠模型中的甲状旁腺过度活跃和肿大。
利用CRISPR/Cas9基因编辑技术构建了一个种系杂合型Gcm2变异p.Y392S的小鼠模型，该变异与人类GCM2基因的p.Y394S变异相对应。对野生型（WT）和种系杂合型（Het）小鼠进行血清生化和甲状旁腺形态学评估。
与WT小鼠相比，Het小鼠在血清钙和甲状旁腺激素水平、甲状旁腺组织学、细胞增殖或甲状旁腺大小方面均未显示出任何变化。
Gcm2基因p.Y392S变异的小鼠模型表明，该变异在小鼠中是可耐受的，因为它不会增加甲状旁腺细胞增殖以及循环钙或甲状旁腺激素水平。进一步研究Gcm2基因变异小鼠，以探讨该变异对甲状旁腺发育早期事件的影响将很有意义。
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