Familial hypocalciuric hypercalcemia causes: Difference between revisions
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{{Familial hypocalciuric hypercalcemia}} | {{Familial hypocalciuric hypercalcemia}} | ||
{{CMG}}; {{AE}} | {{CMG}}; {{AE}}{{Ajay}} | ||
==Overview== | ==Overview== | ||
FHH is caused by a mutation in the | Familial hypocalciuric hypercalcemia (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 [[Renal tubule|kidney tubule]] express CaSR, a [[G protein-coupled receptor|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 3 (human)|chromosome 3]]<nowiki/>p13.3-21 can cause either [[hypercalcemia]] or [[hypocalcemia]]. Inactivating [[mutation]] causes [[hypercalcemia]], whereas the activating [[mutation]] causes [[hypocalcemia]]. [[Heterozygous]] [[loss of function mutation|loss-of-function mutations]] give rise to [[Familial hypocalciuric hypercalcemia|FHH]], an [[asymptomatic]] [[hypercalcemia]]. The [[homozygous]] [[mutation]] manifests as [[neonatal]] severe [[hyperparathyroidism]], a rare [[Disorders|disorder]] characterized by extreme [[hypercalcemia]] and the [[bony changes]] of [[hyperparathyroidism]]. The [[disorder]] is known to be [[autosomal dominant]] [[hypocalcemia]] due to a [[gain of function mutation|gain-of-function mutations]] in the [[CASR|CaSR]] [[gene]]; this may be [[asymptomatic]] or may present with [[seizures]]. The three types of FHH are known to be caused due to different [[genetic]] [[mutations]]. Type-1 FHH is caused by a [[loss of function|loss-of-function mutations]] of the CaSR, a [[G-protein coupled receptor]] that predominantly signals via [[G-protein|G-protein subunit alpha]]-11 (Gα11) to regulate calcium [[homeostasis]] located on [[Chromosome 3 (human)|chromosome 3]]<nowiki/>q13.3-q21. Type-2 FHH is caused by [[heterozygous]] [[mutation]] in the GNA11 gene on [[chromosome]] 19p13. Type-3 FHH is caused by [[heterozygous]] [[mutation]] in the AP2S1 [[gene]] on [[chromosome]] 19q13. | ||
==Causes== | ==Causes== | ||
FHH is an autosomal dominant benign inherited condition caused by inactivating missense | Familial hypocalciuric hypercalcemia (FHH) is an [[autosomal dominant]] [[benign]] [[inherited]] condition caused by inactivating [[Missense mutation|missense mutatio]]<nowiki/>n of the CaSR located on [[chromosome]] 3q. There are three types of [[Familial hypocalciuric hypercalcemia|FHH]]<ref name="pmid25104082">{{cite journal |vauthors=Stratta P, Merlotti G, Musetti C, Quaglia M, Pagani A, Izzo C, Radin E, Airoldi A, Baorda F, Palladino T, Leone MP, Guarnieri V |title=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 |journal=Nephrol. Dial. Transplant. |volume=29 |issue=10 |pages=1902–9 |year=2014 |pmid=25104082 |doi=10.1093/ndt/gfu065 |url=}}</ref><ref name="pmid26963950">{{cite journal |vauthors=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 |title=Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=5 |pages=2185–95 |year=2016 |pmid=26963950 |doi=10.1210/jc.2015-3442 |url=}}</ref><ref name="pmid26729423">{{cite journal |vauthors=Gorvin CM, Cranston T, Hannan FM, Rust N, Qureshi A, Nesbit MA, Thakker RV |title=A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) |journal=J. Bone Miner. Res. |volume=31 |issue=6 |pages=1200–6 |year=2016 |pmid=26729423 |pmc=4949650 |doi=10.1002/jbmr.2778 |url=}}</ref><ref name="pmid23802516">{{cite journal |vauthors=Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, Thakker RV |title=Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia |journal=N. Engl. J. Med. |volume=368 |issue=26 |pages=2476–2486 |year=2013 |pmid=23802516 |pmc=3773604 |doi=10.1056/NEJMoa1300253 |url=}}</ref><ref name="pmid28176280">{{cite journal |vauthors=Szalat A, Shpitzen S, Tsur A, Zalmon Koren I, Shilo S, Tripto-Shkolnik L, Durst R, Leitersdorf E, Meiner V |title=Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia |journal=Endocrine |volume=55 |issue=3 |pages=741–747 |year=2017 |pmid=28176280 |doi=10.1007/s12020-017-1241-5 |url=}}</ref><ref name="pmid24731014">{{cite journal |vauthors=Hendy GN, Canaff L, Newfield RS, Tripto-Shkolnik L, Wong BY, Lee BS, Cole DE |title=Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations |journal=J. Clin. Endocrinol. Metab. |volume=99 |issue=7 |pages=E1311–5 |year=2014 |pmid=24731014 |doi=10.1210/jc.2014-1120 |url=}}</ref><ref name="pmid26646938">{{cite journal |vauthors=Mayr B, Schnabel D, Dörr HG, Schöfl C |title=GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts |journal=Eur. J. Endocrinol. |volume=174 |issue=5 |pages=R189–208 |year=2016 |pmid=26646938 |doi=10.1530/EJE-15-1028 |url=}}</ref><br> | ||
* '''Type-1 FHH''': Loss-of-function [[mutations]] of the [[Calcium-sensing receptor|calcium-sensing receptor (CaSR)]], a [[G protein-coupled receptor|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 FHH''': [[heterozygous]] [[mutation]] in the GNA11 gene on [[chromosome]] 19p13. | |||
* '''Type-3 FHH''': [[heterozygous|Heterozygous]] [[mutation]] in the AP2S1 gene on [[chromosome]] 19q13. | |||
===Genetic Causes=== | ===Genetic Causes=== | ||
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]]. | |||
* The [[chief cells]] of the [[parathyroid gland]] and the lining of the [[Renal tubule|kidney tubule]] express CaSR a [[G protein-coupled receptor|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|CaSR]] [[gene]] located on [[Chromosome 3 (human)|chromosome 3]]<nowiki/>p13.3-21 can cause either [[hypercalcemia]] or [[hypocalcemia]]. | |||
* Inactivating [[mutation]] causes [[hypercalcemia]] whereas the activating [[mutation]] causes [[hypocalcemia]]. | |||
* [[Heterozygous]] [[loss of function mutation|loss-of-function mutations]] give rise to FHH, an [[asymptomatic]] [[hypercalcemia]]. | |||
* The [[homozygous]] condition manifests as [[neonatal]] severe [[hyperparathyroidism]], a rare [[Disorder (medicine)|disorder]] characterized by extreme [[hypercalcemia]] and the [[bone|bony]] changes of [[hyperparathyroidism]]. | |||
* The disorder [[autosomal dominant]] [[hypocalcemia]] is due to [[gain of function|gain-of-function mutations]] in the CaSR [[gene]], this can be [[asymptomatic]] or presents with seizures. | |||
==References== | ==References== | ||
Latest revision as of 13:19, 16 October 2017
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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
Familial hypocalciuric hypercalcemia (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-function 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 is known to be autosomal dominant hypocalcemia due to a gain-of-function mutations in the CaSR gene; this may be asymptomatic or may present with seizures. The three types of FHH are known to be caused due to different genetic mutations. Type-1 FHH is caused by a 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 FHH is caused by heterozygous mutation in the GNA11 gene on chromosome 19p13. Type-3 FHH is caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13.
Causes
Familial hypocalciuric hypercalcemia (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 FHH: 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 FHH: heterozygous mutation in the GNA11 gene on chromosome 19p13.
- Type-3 FHH: 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 chief cells of the parathyroid gland and the lining of 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-function mutations give rise to FHH, an 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.
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.