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Anti-Müllerian hormone receptor, also known as Müllerian Inhibiting Substance Type II Receptor, is a receptor for the anti-Müllerian hormone (AMH). Furthermore, anti-Müllerian hormone receptor type 2 is a protein in humans that is encoded by the AMHR2 gene.[5]
Structure
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AMHR2 belongs to TGF-β type II receptor family and adopts the characteristic three-finger toxin fold. However, it displays a unique extended finger 1 loop (see image) that is critical to effectively binding its ligand, AMH. The palm region and other fingers are also implicated in binding to AMH, but are relatively unremarkable when compared to other TGF-β type II receptors. As such, these interactions do not contribute significantly to the observed ligand specificity for AMH like the finger 1 loop.[6]
Function
editThe gene is present in both men and women. AMHR2 is a Type 2 receptor that binds AMH (Anti-Müllerian hormone). This hormone is responsible for Müllerian Duct regression in vertebrates once the SRY gene has been expressed. Some animals such as jawless fish do not express either AMH or its receptors.[7] High circulating AMH continues on after testis development and is secreted from the Sertoli Cells. It is also expressed in Leydig cells.[8] It has been reported that the loss of function of the AMHR2 gene results in 50% of XY animals to reverse sex to females and also leads to hyperproliferation of mitotically active germ cells, which leads to the sex reversal.[7] AMH binding to the AMHR2 in mammals causes regression of the oviducts, uterus, and upper 2/3 of the vagina.
Clinical significance
editMüllerian inhibiting substance type II receptor (MISIIR), also known as the Anti-Müllerian Hormone Receptor, is expressed by ovarian, breast, and prostate cancers and these cancer cells have been reported to apoptose in response to exposure to the Müllerian inhibiting substance (MIS).[9]
Monoclonal Antibodies have been developed that specifically target MISIIR and may be useful as vehicles for drugs and toxins for targeted cancer therapy.[10][11][12]
A syndrome called "Persistent Mullerian Duct Syndrome" (PMDS) can occur in human males and results in the uterus, vagina, and uterus being present in virilized male.[13] PMDS can be caused by a genetic mutation of deletions, or missenses, and these males often have undescended testes or cryptorchidism, where one testis fails to descend outside of the body cavity. The majority of these patients will be infertile. In females that are homozygous for the mutation, no abnormalities have been observed. However, heterozygous females have been observed to reach menopause sooner and display a lowered AMH level which also is an indicator of antral follicle count. It is likely that these females reach menopause sooner from having fewer antral follicles, thus more atresia of follicles prior to developing an antrum. These phenotypes were confirmed to be the cause of an AMHR2 mutation from knock out studies performed in mice.
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000135409 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023047 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Anti-Mullerian hormone receptor type 2". Retrieved 2018-06-07.
- ^ a b PDB: 7L0J; Hart KN, Stocker WA, Nagykery NG, Walton KL, Harrison CA, Donahoe PK, et al. (June 2021). "Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family". Proceedings of the National Academy of Sciences of the United States of America. 118 (26): e2104809118. Bibcode:2021PNAS..11804809H. doi:10.1073/pnas.2104809118. PMC 8256043. PMID 34155118.
- ^ a b Adolfi MC, Nakajima RT, Nóbrega RH, Schartl M (February 2019). "Intersex, Hermaphroditism, and Gonadal Plasticity in Vertebrates: Evolution of the Müllerian Duct and Amh/Amhr2 Signaling". Annual Review of Animal Biosciences. 7: 149–172. doi:10.1146/annurev-animal-020518-114955. PMID 30303691. S2CID 52954655.
- ^ Salhi I, Cambon-Roques S, Lamarre I, Laune D, Molina F, Pugnière M, et al. (May 2004). "The anti-Müllerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand". The Biochemical Journal. 379 (Pt 3): 785–793. doi:10.1042/bj20031961. PMC 1224123. PMID 14750901.
- ^ Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF, Shah PC, et al. (November 1999). "Human ovarian cancer, cell lines, and primary ascites cells express the human Mullerian inhibiting substance (MIS) type II receptor, bind, and are responsive to MIS". Clinical Cancer Research. 5 (11): 3488–3499. PMID 10589763.
- ^ Yuan QA, Robinson MK, Simmons HH, Russeva M, Adams GP (March 2008). "Isolation of anti-MISIIR scFv molecules from a phage display library by cell sorter biopanning". Cancer Immunology, Immunotherapy. 57 (3): 367–378. doi:10.1007/s00262-007-0376-2. PMC 11031043. PMID 17676323. S2CID 13075446.
- ^ Yuan QA, Simmons HH, Robinson MK, Russeva M, Marasco WA, Adams GP (August 2006). "Development of engineered antibodies specific for the Müllerian inhibiting substance type II receptor: a promising candidate for targeted therapy of ovarian cancer". Molecular Cancer Therapeutics. 5 (8): 2096–2105. doi:10.1158/1535-7163.MCT-06-0115. PMID 16928831.
- ^ Salhi I, Cambon-Roques S, Lamarre I, Laune D, Molina F, Pugnière M, et al. (May 2004). "The anti-Müllerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand". The Biochemical Journal. 379 (Pt 3): 785–793. doi:10.1042/BJ20031961. PMC 1224123. PMID 14750901.
- ^ Mullen RD, Ontiveros AE, Moses MM, Behringer RR (November 2019). "AMH and AMHR2 mutations: A spectrum of reproductive phenotypes across vertebrate species". Developmental Biology. 455 (1): 1–9. doi:10.1016/j.ydbio.2019.07.006. PMC 6754765. PMID 31301298.
- This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Further reading
edit- Teixeira J, Maheswaran S, Donahoe PK (October 2001). "Müllerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications". Endocrine Reviews. 22 (5): 657–674. doi:10.1210/edrv.22.5.0445. PMID 11588147.
- Picard JY, Belville C (2002). "[Genetics and molecular pathology of anti-Mullerian hormone and its receptor]". Journal de la Société de Biologie (in French). 196 (3): 217–221. doi:10.1051/jbio/2002196030217. PMID 12462075.
- Wang HQ, Takakura K, Takebayashi K, Noda Y (December 2002). "Mutational analysis of the müllerian-inhibiting substance gene and its receptor gene in Japanese women with polycystic ovary syndrome and premature ovarian failure". Fertility and Sterility. 78 (6): 1329–1330. doi:10.1016/s0015-0282(02)04351-0. PMID 12477536.
- Salhi I, Cambon-Roques S, Lamarre I, Laune D, Molina F, Pugnière M, et al. (May 2004). "The anti-Müllerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand". The Biochemical Journal. 379 (Pt 3): 785–793. doi:10.1042/BJ20031961. PMC 1224123. PMID 14750901.
- Kevenaar ME, Themmen AP, Laven JS, Sonntag B, Fong SL, Uitterlinden AG, et al. (June 2007). "Anti-Müllerian hormone and anti-Müllerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women". Human Reproduction. 22 (6): 1547–1554. doi:10.1093/humrep/dem036. PMID 17337470.
- Kevenaar ME, Themmen AP, Laven JS, Sonntag B, Fong SL, Uitterlinden AG, et al. (June 2007). "Anti-Müllerian hormone and anti-Müllerian hormone type II receptor polymorphisms are associated with follicular phase estradiol levels in normo-ovulatory women". Human Reproduction. 22 (6): 1547–1554. doi:10.1093/humrep/dem036. PMID 17337470.
- Kevenaar ME, Themmen AP, Rivadeneira F, Uitterlinden AG, Laven JS, van Schoor NM, et al. (September 2007). "A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity". Human Reproduction. 22 (9): 2382–2388. doi:10.1093/humrep/dem176. PMID 17636279.
- Kevenaar ME, Themmen AP, Rivadeneira F, Uitterlinden AG, Laven JS, van Schoor NM, et al. (September 2007). "A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity". Human Reproduction. 22 (9): 2382–2388. doi:10.1093/humrep/dem176. PMID 17636279.
- Bakkum-Gamez JN, Aletti G, Lewis KA, Keeney GL, Thomas BM, Navarro-Teulon I, Cliby WA (January 2008). "Müllerian inhibiting substance type II receptor (MISIIR): a novel, tissue-specific target expressed by gynecologic cancers". Gynecologic Oncology. 108 (1): 141–148. doi:10.1016/j.ygyno.2007.09.010. PMID 17988723.
External links
edit- Anti-Mullerian+hormone+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
