Spatial transcriptomics of mouse parathyroid gland cells expressing an activating variant of Gcm2

Authors

• P Bolel
• JO Piña
• FR Faucz
• LS Weinstein
• SK Agarwal

Abstract

Tumors of one or multiple parathyroid glands and elevated serum calcium and parathyroid hormone (PTH) are the common characteristics of primary hyperparathyroidism (PHPT). The glial cells missing 2 (GCM2) gene is essential for parathyroid gland development. Heterozygous germline missense variants located within the C-terminal conserved inhibitory domain (CCID) of GCM2 have been reported in a subset of patients with PHPT. In functional assays, these missense variants enhance the transcriptional activity of GCM2, suggesting that GCM2 could act as a proto-oncogene in parathyroid neoplasia. A recurrent germline activating missense variant of GCM2, p.Y394S in patients with PHPT has been reported in various publications. To study the direct contribution of this missense variant in parathyroid neoplasia, we used the CRISPR/Cas9 system to generate a heterozygous germline knock-in of p.Y392S in the mouse Gcm2 gene (which corresponds to the human variant p.Y394S in GCM2). Although the mouse Gcm2 variant p.Y392S also enhanced transcription, mice with this variant (Gcm2+/Y392S) did not show obvious parathyroid tumors. Using the 10X Genomics Visium platform, spatially resolved RNA-seq analysis was performed on parathyroid gland cells of WT and Gcm2+/Y392S mice specifically marked by the expression of Pth and Gcm2. Spatial transcriptomics and Pathway analysis was performed to evaluate transcripts with more than 2-fold increased expression in parathyroid cells from the p.Y392S variant of Gcm2 compared to WT. Further investigation of these genes and pathways in mouse and human parathyroid cells can provide insights into the functional consequences of GCM2 activating variants and the pathophysiology of parathyroid tumorigenesis.

Scientific Focus Area: Cancer Biology

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