GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

Am J Hum Genet. 2016 Nov 3;99(5):1034-1044. doi: 10.1016/j.ajhg.2016.08.018. Epub 2016 Oct 13.


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.

MeSH terms

  • Adenoma / diagnosis
  • Adenoma / genetics*
  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Exome
  • Female
  • Fibroma / diagnosis
  • Fibroma / genetics*
  • Genetic Variation
  • Germ-Line Mutation*
  • Humans
  • Hyperparathyroidism / diagnosis
  • Hyperparathyroidism / genetics*
  • Hyperparathyroidism, Primary / diagnosis
  • Hyperparathyroidism, Primary / genetics*
  • Jaw Neoplasms / diagnosis
  • Jaw Neoplasms / genetics*
  • Male
  • Middle Aged
  • Multiple Endocrine Neoplasia Type 1 / diagnosis
  • Multiple Endocrine Neoplasia Type 1 / genetics*
  • Nuclear Proteins / genetics*
  • Parathyroid Hormone
  • Pedigree
  • Proto-Oncogene Mas
  • Proto-Oncogenes / genetics
  • Sequence Analysis, DNA
  • Transcription Factors / genetics*
  • Young Adult


  • GCM2 protein, human
  • MAS1 protein, human
  • Nuclear Proteins
  • Parathyroid Hormone
  • Proto-Oncogene Mas
  • Transcription Factors

Supplementary concepts

  • Hyperparathyroidism 1
  • Hyperparathyroidism 2