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AMHR2
anti-Mullerian hormone receptor type 2
The AMHR2 gene provides instructions for the anti-Müllerian hormone receptor type 2, a protein crucial for male reproductive development by signalling the regression of Müllerian ducts. AMHR2 plays a key role in sexual differentiation during foetal development.
AMHR2 is located on the long (q) arm of chromosome 12, at band 12q13.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The AMHR2 gene encodes the anti-Müllerian hormone receptor type 2, a protein vital for typical male sexual development. During foetal development, cells of the Müllerian ducts express this receptor on their surface. These embryonic structures exist in all foetuses regardless of chromosomal sex.
In male foetuses, the testes produce anti-Müllerian hormone (AMH), which binds to the AMHR2 receptor. This binding initiates a signalling pathway that leads to the breakdown of the Müllerian ducts, preventing the development of female reproductive organs. In female foetuses, AMH is not produced, allowing the Müllerian ducts to develop into the uterus and fallopian tubes.
What the gene does
The AMHR2 gene provides instructions for synthesising the anti-Müllerian hormone receptor type 2. This receptor is a transmembrane protein primarily found on the cells of the Müllerian ducts during foetal development. Its main function is to mediate the cellular response to anti-Müllerian hormone (AMH).
Testicular cells in male foetuses produce AMH, which engages the AMHR2 receptor and activates intracellular pathways that ultimately cause Müllerian duct cells to undergo programmed death [PMID:20301490]. This eliminates these embryonic structures before they can form female organs. Female foetuses do not synthesise AMH, so these embryonic ducts remain intact and differentiate into the upper reproductive tract, including the uterine body and oviducts [PMID:18209890].
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Chromosome location
The AMHR2 gene is situated on chromosome 12 at position 12q13.13. This location refers to the long arm (q) of chromosome 12, specifically within region 13 and sub-band 13. This genomic address precisely defines the gene's physical place within the human genome.
Protein structure
The AMHR2 protein consists of 573 amino acids. A key functional region within the AMHR2 protein is the Protein kinase domain, located between amino acid positions 203 and 518. This domain is crucial for the receptor's ability to transmit signals inside the cell once anti-Müllerian hormone has bound to it.
Key variants
Genetic variations within the AMHR2 gene can alter the function of the anti-Müllerian hormone receptor type 2. These variants can include changes to single DNA building blocks (missense variants), small insertions or deletions, or larger structural rearrangements. Such changes may impair the receptor's ability to bind AMH or transmit signals, leading to developmental conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1219C>T | p.Arg407Ter | Pathogenic | ★★☆☆ | AMHR2-related disorder |
c.1332_1358del | p.Gly445_Leu453del | Pathogenic | ★★☆☆ | AMHR2-related disorder |
c.1387C>T | p.Arg463Cys | Pathogenic/Likely pathogenic | ★★☆☆ | AMHR2-related disorder |
c.1412G>A | p.Arg471His | Pathogenic/Likely pathogenic | ★★☆☆ | Persistent Mullerian duct syndrome |
c.502G>A | p.Ala168Thr | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.514C>T | p.Arg172Ter | Pathogenic/Likely pathogenic | ★★☆☆ | AMHR2-related disorder |
c.64C>T | p.Arg22Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Persistent Mullerian duct syndrome |
c.1140+1G>A | - | Pathogenic | ★☆☆☆ | not provided |
c.175del | p.Arg59fs | Pathogenic | ★☆☆☆ | not provided |
c.261_262del | p.Cys87_Glu88delinsTer | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the AMHR2 gene are associated with inherited conditions primarily affecting male sexual development. The most well-characterised condition linked to AMHR2 variants is Persistent Müllerian duct syndrome. This condition typically affects males and results in the presence of female reproductive organs alongside normal male reproductive structures.
UK clinical status
The AMHR2 gene is recognised within the UK's NHS Genomic Medicine Service. It is included on the 'Differences in sex development' PanelApp panel, where it holds a 'green' status, indicating strong evidence for its association with relevant conditions (R146).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of the AMHR2 gene in foetal development?
The AMHR2 gene provides instructions for a receptor that is crucial for male sex differentiation. It signals the regression of Müllerian ducts in male foetuses, preventing the development of female reproductive organs.
What happens if there are variants in the AMHR2 gene?
Variants in the AMHR2 gene can impair the function of the anti-Müllerian hormone receptor type 2. This can lead to conditions such as Persistent Müllerian duct syndrome, where males may develop both male and female internal reproductive organs.
Is the AMHR2 gene associated with conditions in females?
While AMHR2 is critical for male reproductive development, its primary known association with inherited conditions, such as Persistent Müllerian duct syndrome, affects males. In females, the Müllerian ducts normally develop into the uterus and fallopian tubes in the absence of AMH signalling.
References
- Josso N, Belville C, di Clemente N. AMH and AMH receptor defects in persistent Müllerian duct syndrome. Human reproduction update. 2005. PMID: 15878900
- Rey R. Anti-Müllerian hormone in disorders of sex determination and differentiation. Arquivos brasileiros de endocrinologia e metabologia. 2005. PMID: 16544032
- Josso N, Picard JY, Imbeaud S. Clinical aspects and molecular genetics of the persistent müllerian duct syndrome. Clinical endocrinology. 1997. PMID: 9302384
- Imbeaud S, Belville C, Messika-Zeitoun L. A 27 base-pair deletion of the anti-müllerian type II receptor gene is the most common cause of the persistent müllerian duct syndrome. Human molecular genetics. 1996. PMID: 8872466
- Faure E, Gouédard L, Imbeaud S. Mutant isoforms of the anti-Müllerian hormone type II receptor are not expressed at the cell membrane. The Journal of biological chemistry. 1996. PMID: 8940028