This report describes characterization of a mutation implicated in hypoparathyroidism, familial isolated (FIH), GCM2-related; this disease exhibits autosomal dominant inheritance. The human gene implicated in this disease is glial cells missing homolog 2 (GCM2), which is a transcription factor necessary for multiple developmental decisions, including for parathyroid development. GCM2 is one of two paralogous genes in human (the other is GCM1); there are also two paralogous genes in Drosophila (gcm and gcm2).
GCM transcription factors affect developmental decisions in both mammals and flies, but in somewhat different contexts: in mammals, they mediate neural stem cell induction, placenta and parathyroid development; in Drosophila they play a role in determination of neuronal and glial cell fates and regulate hemocyte development.
UAS constructs of the human Hsap\GCM2 have been introduced into flies, including wild-type and a variant associated with hypoparathyroidism. The same variant has been introduced into the fly gcm gene. Variant(s) implicated in human disease tested (as transgenic human gene, GCM2): the R47L variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R59L in the fly gcm gene (corresponds to R47L in the human GCM2 gene). In both cases, phenotypes mediated by the variant proteins are consistent with reduced function. The gcm variant protein is shown to be less stable than wild-type and to become hyperubiquitinated.
[updated Jul. 2019 by FlyBase; FBrf0222196]
[HYPOPARATHYROIDISM, FAMILIAL ISOLATED, 2; FIH2](https://omim.org/entry/618883)
[GLIAL CELLS MISSING TRANSCRIPTION FACTOR 2; GCM2](https://omim.org/entry/603716)
Patients with familial isolated hypoparathyroidism-2 (FIH2) usually present with seizures, caused by hypocalcemia, in early life. Serum parathyroid hormone (PTH) levels are low to undetectable. Hyperphosphatemia is present, and levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D may be within the normal range. Development can be normal if hypocalcemia is treated with calcium and vitamin D supplementation (Ding et al., 2001; pubmed:11602629). Some patients have been found to lack parathyroid glands (Thomee et al., 2005; pubmed:15728199). [from MIM:618883; 2025.06.02]
Hypoparathyroidism is the state of decreased secretion or activity of parathyroid hormone (PTH). This leads to decreased blood levels of calcium (hypocalcemia) and increased levels of blood phosphorus (hyperphosphatemia). Symptoms can range from quite mild (tingling in the hands, fingers, and around the mouth) to more severe forms of muscle cramps. The most severe symptoms are tetany (severe muscle cramping of the entire body) and convulsions (very rare). (https://www.endocrineweb.com/conditions/hypoparathyroidism/hypoparathyroidism)
Familial isolated hypoparathyroidism-2 (FIH2) is caused by homozygous mutation in the glial cells missing transcription factor-2 gene (GCM2) on chromosome 6p24. Some patients have been reported with heterozygous mutations in the GCM2 gene. [from MIM:618883; 2025.06.02]
Mammalian GCM proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila GCM proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development (FBrf0234439 and references cited therein).
The protein encoded by GCM2 (Glial Cells Missing Homolog 2) is a transcription factor that is necessary for parathyroid development; it contains a conserved N-terminal GCM motif that has DNA-binding activity. [Gene Cards, GCM2; 2018.04.18]
Many to many: 2 human to 2 Drosophila; the second human gene is GCM1.
Moderate- to high-scoring ortholog of human GCM2 and GCM1 (2 Drosophila to 2 human). Dmel\gcm shares 31-32% identity and 46-47% similarity with the human genes.
