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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 crucial protein in male sex development that facilitates the regression of Müllerian ducts during foetal development. AMHR2 is a gene that codes for the anti-Müllerian hormone receptor type 2, an important component in the signalling pathway that directs the development of male reproductive organs.
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 provides the genetic blueprint for the anti-Müllerian hormone receptor type 2. This receptor is vital for typical male sexual differentiation during foetal development, as it responds to anti-Müllerian hormone (AMH) [PMID:16738596].
Within a clinical context, the AMHR2 gene is categorised under Endocrine conditions and is included in NHS genomic panels for evaluation.
What the gene does
The AMHR2 gene carries the instructions for producing the anti-Müllerian hormone receptor type 2 protein. This receptor is found on the cell surfaces of Müllerian ducts, which are embryonic structures present in both male and female foetuses and serve as precursors to female reproductive organs.
In male foetuses, the testes produce the AMH protein. This protein then binds to the AMH receptor type 2, initiating a signalling pathway that leads to the programmed destruction, or apoptosis, of the Müllerian duct cells [PMID:16738596]. This process ensures the ducts regress in males. In contrast, female foetuses do not produce AMH during development, allowing the Müllerian ducts to develop into the uterus and fallopian tubes [PMID:11897769].
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Chromosome location
The AMHR2 gene is situated on chromosome 12 at position 12q13.13. This specific location within the human genome defines its address. The gene codes for a protein composed of 573 amino acids.
Protein structure
The AMHR2 protein, also known as the anti-Müllerian hormone receptor type 2, features a significant Protein kinase domain. This domain spans amino acids 203 to 518 and is essential for the protein's ability to transmit signals. It enables the receptor to relay information from the bound anti-Müllerian hormone into the cell, thereby orchestrating cellular responses.
Key variants
Genetic changes within the AMHR2 gene can impair the function of the anti-Müllerian hormone receptor type 2. These alterations may affect the protein's capacity to bind AMH or to properly initiate the signalling cascade required for Müllerian duct regression. At least 24 mutations in the AMHR2 gene have been identified in individuals with associated 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.1332_1358del | p.Gly445_Leu453del | Pathogenic | ★★☆☆ | Differences in sex development |
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 | ★★☆☆ | Persistent Mullerian duct syndrome |
c.64C>T | p.Arg22Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Persistent Mullerian duct syndrome |
c.1140+1G>A | - | Pathogenic | ★☆☆☆ | not provided |
c.1219C>T | p.Arg407Ter | Pathogenic | ★☆☆☆ | Persistent Mullerian duct syndrome |
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 linked to Persistent Müllerian duct syndrome, a disorder affecting sexual development in individuals assigned male at birth. This condition follows an autosomal recessive inheritance pattern. Males with Persistent Müllerian duct syndrome typically develop both male and female reproductive organs because the Müllerian ducts fail to regress during foetal development.
- Persistent Müllerian duct syndrome Dedicated page coming soon
UK clinical status
The AMHR2 gene is part of the UK's NHS Genomic Medicine Service. It is listed on the 'Differences in sex development' panel (R146), which is classified as green, indicating robust evidence for its association with relevant conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the AMHR2 gene?
The AMHR2 gene provides instructions for the anti-Müllerian hormone receptor type 2, which is essential for male sex differentiation. It helps in the regression of Müllerian ducts in male foetuses, preventing the development of female reproductive organs.
What condition is associated with variants in the AMHR2 gene?
Variants in the AMHR2 gene are primarily associated with Persistent Müllerian duct syndrome. This condition affects males, who may present with both male and female reproductive organs due to the Müllerian ducts not regressing properly during development.
How does the AMHR2 receptor work during foetal development?
In male foetuses, the AMHR2 receptor on Müllerian duct cells binds to anti-Müllerian hormone (AMH). This binding triggers a signalling cascade that leads to the elimination of these ducts, ensuring normal male reproductive organ development.
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