Anti-Müllerian hormone receptor explained

Anti-Müllerian hormone receptor is a receptor for the anti-Müllerian hormone. Furthermore, anti-Müllerian hormone receptor type 2 is a protein in humans that is encoded by the AMHR2 gene.^[1]

Function

Both men and women have this gene. 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 AMHR2.^[2] High circulating AMH continues on after testis development and is secreted from the Sertoli Cells. 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. AMH binding to the AMHR2 in mammals causes regression of the oviducts, uterus, and upper 2/3 of the vagina. 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.^[3] 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.

Structure

^[4]

AMHR2 adopts a typical three-finger toxin fold that is characteristic of the TGF-β type II receptor family to which it belongs. 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.

Pathology

The anti-Müllerian hormone receptor (Müllerian Inhibiting Substance Type II Receptor) can be responsible for persistent Müllerian duct syndrome.

Müllerian 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).^[5]

Antibodies have been developed that specifically target MISIIR and may be useful as vehicles for drugs and toxins for targeted cancer therapy.^{[6] [7] [8]}

Further reading

• Teixeira J, Maheswaran S, Donahoe PK . Müllerian inhibiting substance: an instructive developmental hormone with diagnostic and possible therapeutic applications . Endocrine Reviews . 22 . 5 . 657–674 . October 2001 . 11588147 . 10.1210/edrv.22.5.0445 . free .
• Picard JY, Belville C . [Genetics and molecular pathology of anti-Mullerian hormone and its receptor] . fr . Journal de la Société de Biologie . 196 . 3 . 217–221 . 2002 . 12462075 . 10.1051/jbio/2002196030217 .
• Wang HQ, Takakura K, Takebayashi K, Noda Y . 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 . December 2002 . 12477536 . 10.1016/s0015-0282(02)04351-0 . free .
• Salhi I, Cambon-Roques S, Lamarre I, Laune D, Molina F, Pugnière M, Pourquier D, Gutowski M, Picard JY, Xavier F, Pèlegrin A, Navarro-Teulon I . 6 . 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 . May 2004 . 14750901 . 1224123 . 10.1042/BJ20031961 .
• Kevenaar ME, Themmen AP, Laven JS, Sonntag B, Fong SL, Uitterlinden AG, de Jong FH, Pols HA, Simoni M, Visser JA . 6 . 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 . June 2007 . 17337470 . 10.1093/humrep/dem036 . free .
• Kevenaar ME, Themmen AP, Laven JS, Sonntag B, Fong SL, Uitterlinden AG, de Jong FH, Pols HA, Simoni M, Visser JA . 6 . 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 . June 2007 . 17337470 . 10.1093/humrep/dem036 . free .
• Kevenaar ME, Themmen AP, Rivadeneira F, Uitterlinden AG, Laven JS, van Schoor NM, Lips P, Pols HA, Visser JA . 6 . 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 . September 2007 . 17636279 . 10.1093/humrep/dem176 . free .
• Kevenaar ME, Themmen AP, Rivadeneira F, Uitterlinden AG, Laven JS, van Schoor NM, Lips P, Pols HA, Visser JA . 6 . 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 . September 2007 . 17636279 . 10.1093/humrep/dem176 . free .
• Bakkum-Gamez JN, Aletti G, Lewis KA, Keeney GL, Thomas BM, Navarro-Teulon I, Cliby WA . Müllerian inhibiting substance type II receptor (MISIIR): a novel, tissue-specific target expressed by gynecologic cancers . Gynecologic Oncology . 108 . 1 . 141–148 . January 2008 . 17988723 . 10.1016/j.ygyno.2007.09.010 .

Notes and References

1. Web site: Entrez Gene: Anti-Mullerian hormone receptor type 2. 2018-06-07.
2. Adolfi MC, Nakajima RT, Nóbrega RH, Schartl M . Intersex, Hermaphroditism, and Gonadal Plasticity in Vertebrates: Evolution of the Müllerian Duct and Amh/Amhr2 Signaling . Annual Review of Animal Biosciences . 7 . 149–172 . February 2019 . 30303691 . 10.1146/annurev-animal-020518-114955 . 52954655 .
3. Mullen RD, Ontiveros AE, Moses MM, Behringer RR . AMH and AMHR2 mutations: A spectrum of reproductive phenotypes across vertebrate species . Developmental Biology . 455 . 1 . 1–9 . November 2019 . 10.1016/j.ydbio.2019.07.006 . 31301298 . 6754765 .
4. Hart KN, Stocker WA, Nagykery NG, Walton KL, Harrison CA, Donahoe PK, Pépin D, Thompson TB . 6 . 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 . June 2021 . 34155118 . 8256043 . 10.1073/pnas.2104809118 . 2021PNAS..11804809H . free .
5. Masiakos PT, MacLaughlin DT, Maheswaran S, Teixeira J, Fuller AF, Shah PC, Kehas DJ, Kenneally MK, Dombkowski DM, Ha TU, Preffer FI, Donahoe PK . 6 . 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 . November 1999 . 10589763 .
6. Yuan QA, Robinson MK, Simmons HH, Russeva M, Adams GP . Isolation of anti-MISIIR scFv molecules from a phage display library by cell sorter biopanning . Cancer Immunology, Immunotherapy . 57 . 3 . 367–378 . March 2008 . 17676323 . 10.1007/s00262-007-0376-2 . 13075446 . 11031043 .
7. Yuan QA, Simmons HH, Robinson MK, Russeva M, Marasco WA, Adams GP . 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 . August 2006 . 16928831 . 10.1158/1535-7163.MCT-06-0115 . free .
8. Salhi I, Cambon-Roques S, Lamarre I, Laune D, Molina F, Pugnière M, Pourquier D, Gutowski M, Picard JY, Xavier F, Pèlegrin A, Navarro-Teulon I . 6 . 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 . May 2004 . 14750901 . 1224123 . 10.1042/BJ20031961 .