Familial hypocalciuric hypercalcemia causes: Difference between revisions
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* Type-3: caused by [[heterozygous]] [[mutation]] in the AP2S1 gene on [[chromosome]] 19q13. | * Type-3: caused by [[heterozygous]] [[mutation]] in the AP2S1 gene on [[chromosome]] 19q13. | ||
===Genetic Causes=== | ===Genetic Causes=== | ||
The genetic causes are as follows | The genetic causes are as follows<ref name="pmid11013439">{{cite journal |vauthors=Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE |title=Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia |journal=Hum. Mutat. |volume=16 |issue=4 |pages=281–96 |year=2000 |pmid=11013439 |doi=10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A |url=}}</ref><ref name="pmid15241791">{{cite journal |vauthors=Pidasheva S, D'Souza-Li L, Canaff L, Cole DE, Hendy GN |title=CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia |journal=Hum. Mutat. |volume=24 |issue=2 |pages=107–11 |year=2004 |pmid=15241791 |doi=10.1002/humu.20067 |url=}}</ref><ref name="pmid15662592">{{cite journal |vauthors=Felderbauer P, Hoffmann P, Klein W, Bulut K, Ansorge N, Epplen JT, Schmitz F, Schmidt WE |title=Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis |journal=Exp. Clin. Endocrinol. Diabetes |volume=113 |issue=1 |pages=31–4 |year=2005 |pmid=15662592 |doi=10.1055/s-2004-830523 |url=}}</ref>: | ||
*FHH is caused by a [[mutation]] in the CASR gene located on [[chromosome 3]]. | *FHH is caused by a [[mutation]] in the CASR gene located on [[chromosome 3]]. | ||
* The [[calcium-sensing receptor]] is a [[plasma membrane]] [[G protein-coupled receptor]] that is expressed on the [[Chief cell|chief cells]] of the [[parathyroid gland]] and the lining the [[Renal tubule|kidney tubule]]. | * The [[calcium-sensing receptor]] is a [[plasma membrane]] [[G protein-coupled receptor]] that is expressed on the [[Chief cell|chief cells]] of the [[parathyroid gland]] and the lining the [[Renal tubule|kidney tubule]]. | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]
Overview
FHH is caused by a mutation in the calcium-sensing receptor (CASR) gene located on the chromosome 3. The chief cells of the parathyroid gland and the lining the kidney tubule express CASR a G protein coupled plasma membrane receptor which has the ability to sense small changes in circulating calcium concentration.This information is sent to intracellular signaling pathways that modify PTH secretion or renal calcium handling. Inherited abnormalities of the CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia. Inactivating mutation causes hypercalcemia whereas the activating mutation causes hypocalcemia. Heterozygous loss-of-functional mutations give rise to FHH, an asymptomatic hypercalcemia. The homozygous mutation manifests as neonatal severe hyperparathyroidism, a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism. The disorder autosomal dominant hypocalcemia is due to gain-of-function mutations in the CASR gene, this can be asymptomatic or presents with seizures. FHH is classified into three types Type-1: caused by loss-of-function mutations of the CASR, a G-protein coupled receptor that predominantly signals via G-protein subunit alpha-11 (Gα11) to regulate calcium homeostasis located on chromosome 3q13.3-q21. Type-2: caused by heterozygous mutation in the GNA11 gene on chromosome 19p13. Type-3: caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13.
Causes
FHH is an autosomal dominant benign inherited condition caused by inactivating missense mutation of the CASR located on chromosome 3q. There are three types of FHH[1][2][3][4][5][6][7]
- Type-1: caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), a G-protein coupled receptor that predominantly signals via G-protein subunit alpha-11 (Gα11) to regulate calcium homeostasis located on chromosome 3q13.3-q21.
- Type-2: caused by heterozygous mutation in the GNA11 gene on chromosome 19p13.
- Type-3: caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13.
Genetic Causes
The genetic causes are as follows[8][9][10]:
- FHH is caused by a mutation in the CASR gene located on chromosome 3.
- The calcium-sensing receptor is a plasma membrane G protein-coupled receptor that is expressed on the chief cells of the parathyroid gland and the lining the kidney tubule.
- CASR has the ability to sense small changes in circulating calcium concentration and send this information to intracellular signaling pathways that modify PTH secretion or renal calcium handling.
- Inherited abnormalities of the CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating.
- Heterozygous loss-of-functional mutations give rise to FHH, a lifelong asymptomatic hypercalcemia.
- The homozygous condition manifests as neonatal severe hyperparathyroidism, a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism.
- The disorder autosomal dominant hypocalcemia is due to gain-of-function mutations in the CASR gene, this can be asymptomatic or presents with seizures.
- A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals.
References
- ↑ Stratta P, Merlotti G, Musetti C, Quaglia M, Pagani A, Izzo C, Radin E, Airoldi A, Baorda F, Palladino T, Leone MP, Guarnieri V (2014). "Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population". Nephrol. Dial. Transplant. 29 (10): 1902–9. doi:10.1093/ndt/gfu065. PMID 25104082.
- ↑ Vargas-Poussou R, Mansour-Hendili L, Baron S, Bertocchio JP, Travers C, Simian C, Treard C, Baudouin V, Beltran S, Broux F, Camard O, Cloarec S, Cormier C, Debussche X, Dubosclard E, Eid C, Haymann JP, Kiando SR, Kuhn JM, Lefort G, Linglart A, Lucas-Pouliquen B, Macher MA, Maruani G, Ouzounian S, Polak M, Requeda E, Robier D, Silve C, Souberbielle JC, Tack I, Vezzosi D, Jeunemaitre X, Houillier P (2016). "Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences". J. Clin. Endocrinol. Metab. 101 (5): 2185–95. doi:10.1210/jc.2015-3442. PMID 26963950.
- ↑ Gorvin CM, Cranston T, Hannan FM, Rust N, Qureshi A, Nesbit MA, Thakker RV (2016). "A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)". J. Bone Miner. Res. 31 (6): 1200–6. doi:10.1002/jbmr.2778. PMC 4949650. PMID 26729423.
- ↑ Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, Thakker RV (2013). "Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia". N. Engl. J. Med. 368 (26): 2476–2486. doi:10.1056/NEJMoa1300253. PMC 3773604. PMID 23802516.
- ↑ Szalat A, Shpitzen S, Tsur A, Zalmon Koren I, Shilo S, Tripto-Shkolnik L, Durst R, Leitersdorf E, Meiner V (2017). "Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia". Endocrine. 55 (3): 741–747. doi:10.1007/s12020-017-1241-5. PMID 28176280.
- ↑ Hendy GN, Canaff L, Newfield RS, Tripto-Shkolnik L, Wong BY, Lee BS, Cole DE (2014). "Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations". J. Clin. Endocrinol. Metab. 99 (7): E1311–5. doi:10.1210/jc.2014-1120. PMID 24731014.
- ↑ Mayr B, Schnabel D, Dörr HG, Schöfl C (2016). "GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts". Eur. J. Endocrinol. 174 (5): R189–208. doi:10.1530/EJE-15-1028. PMID 26646938.
- ↑ Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE (2000). "Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia". Hum. Mutat. 16 (4): 281–96. doi:10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A. PMID 11013439.
- ↑ Pidasheva S, D'Souza-Li L, Canaff L, Cole DE, Hendy GN (2004). "CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia". Hum. Mutat. 24 (2): 107–11. doi:10.1002/humu.20067. PMID 15241791.
- ↑ Felderbauer P, Hoffmann P, Klein W, Bulut K, Ansorge N, Epplen JT, Schmitz F, Schmidt WE (2005). "Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis". Exp. Clin. Endocrinol. Diabetes. 113 (1): 31–4. doi:10.1055/s-2004-830523. PMID 15662592.