GCM2 -Activating Mutations in Familial Isolated Hyperparathyroidism

Abstract

Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.

Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma

“…Recently, activating mutations of the glial cells missing 2 ( GCM2 ) gene, located on chromosome 6p24.2, have been reported in FIHP patients (Guan et al., ). GCM2 encodes a protein that acts as a transcription factor regulating parathyroid development and may also act to regulate the effect of calcium on PTH expression and secretion by parathyroid cells (Kamitani‐Kawamoto et al., ; Han, Tsunekage, & Kataoka, ).…”

The future: genetics advances in MEN1 therapeutic approaches and management strategies

“…Identification of the susceptibility gene for the hyperparathyroidism-jaw tumor syndrome by a positional cloning approach has shown that germline mutations in the CDC73 gene are causative for parathyroid cancer (Carpten, et al 2002; Shattuck, et al 2003). An exome sequencing approach has shown that germline activating mutations in the GCM2 gene occur in 18% of FIHP kindreds (Guan, et al 2016). Germline mutations in the AIP tumor suppressor gene identified by a positional cloning approach, which is also located on 11q13, occur in 20% of FIPA patients and in 30–50% of patients with familial acromegaly, and germline GPR101 microduplication or mutation occurs in patients with X-linked acrogigantism (X-LAG) (Daly, et al 2007; Trivellin, et al 2014; Vierimaa, et al 2006).…”

Diseases associated with calcium-sensing receptor

“…There are also other autosomal dominant genetic forms of familial hypercalcaemia, which are associated with different syndromic manifestations such as tumours and particularly hyperparathyroidism linked to tumour suppressor gene mutations, including:the MEN1 gene, coding for menin in multiple endocrine neoplasia type 1 (MEN1),the HRPT2 (/CDC73) gene , specifically involved in carcinogenesis,the CDKN1B gene , but also the APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, and WT1 genes, and possibly CASR [28], GNA11 , AP2S1, and GCM2 or glial cells Missing-2, a transcription factor linked to the early development pf parathyroid glands [1, 29]as well as mutations of proto-oncogenes ( CCND1/PRAD1 , RET in MEN2, ZFX , CTNNB1 , EZH2 ) [30–32]. …”

“…but also the APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, and WT1 genes, and possibly CASR [28], GNA11 , AP2S1, and GCM2 or glial cells Missing-2, a transcription factor linked to the early development pf parathyroid glands [1, 29]…”