Alternative titles; symbols
HGNC Approved Gene Symbol: AMHR2
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38): 12:53,423,855-53,431,672 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | Persistent Mullerian duct syndrome, type II | 261550 | Autosomal recessive | 3 |
The AMH receptor (AMHR or AMHR2) is a serine/threonine kinase with a single transmembrane domain belonging to the family of type II receptors for TGF-beta-related proteins. Type II receptors bind the ligand on their own but require the presence of a type I receptor for signal transduction. Imbeaud et al. (1995) cloned the human AMH type II receptor gene. The human AMH receptor protein consists of 573 amino acids: 17, 127, 26, and 403 of the 573 amino acids form a signal sequence, extracellular domain (ECD), transmembrane domain, and intracellular domain containing a serine/threonine kinase domain, respectively.
Imbeaud et al. (1995) found that the AMHR gene has 11 exons. Exons 1 to 3 code for the signal sequence and extracellular domain of the receptor, exon 4 corresponds to most of the transmembrane domain, and exons 5 to 11 encode the intracellular serine/threonine kinase domain.
By isotopic in situ hybridization, Imbeaud et al. (1995) determined that the AMHR2 gene is located on 12q13. By haplotype analysis of intersubspecific backcross progeny, Kunieda et al. (1998) mapped the mouse Amhr2 gene to chromosome 15.
Male sex differentiation is mediated by 2 discrete hormones produced by the fetal testis. Testosterone is produced by Leydig cells and both virilizes the external genitalia and promotes prostatic growth, while anti-mullerian hormone (AMH; 600957), also called mullerian inhibiting substance (MIS) or factor (MIF), is produced by the Sertoli cells and results in regression of mullerian ducts which would otherwise differentiate into the uterus and fallopian tubes. Imbeaud et al. (1995) noted that the persistent mullerian duct syndrome (PMDS; 261550), characterized by the presence of mullerian derivatives in otherwise normally virilized males, is sometimes due to mutations in the AMH gene which abrogate AMH production by the immature Sertoli cells. However, the AMH gene and AMH serum levels are normal in approximately half the patients with PMDS, suggesting the existence of target organ insensitivity.
Imbeaud et al. (1995) found that 2 of 3 granulosa cell tumors tested expressed both AMH and the receptor, while an ovarian adenocarcinoma and endometrium did not. Tissues from placenta, uterine cervix, liver, and breast, as well as tumors of uterus, liver, and breast, also gave negative results. It appeared to the authors that the human AMH receptor does not undergo alternative splicing.
Imbeaud et al. (1995) identified a mutation in the AMH receptor (600956.0001) in a patient with persistent mullerian duct syndrome, thus providing genetic evidence that AMHR is required for mullerian regression in the human male. They cloned and sequenced a genomic fragment amplified by SSCP-PCR exhibiting abnormal migration and found a point mutation affecting the invariant GT dinucleotide at the splice donor site of the 5-prime end of intron 2. The mutation resulted in 2 incorrect mRNA species due to alternative splicing, in one case leading to a single amino acid change (gly78-to-asp) followed by the insertion of 4 new residues, EWQR, at the end of exon 2. The patient was homozygous and his parents heterozygous for the mutation.
Imbeaud et al. (1996) reported results of molecular studies on 38 families with PMDS. They identified the basis of the condition, namely 16 AMH and 16 AMHR mutations in 32 families. In prepubertal individuals the type of genetic defect leading to PMDS could be predicted from the level of serum AMH, which is very low or undetectable in PMDS type I due to AMH mutations and at the upper limit of normal in receptor mutations. AMH receptor mutations leading to type II PMDS were detected in 16 patients and 10 of these patients had a 27-bp deletion in exon 10 on at least one allele (600956.0002). This deletion is thus implicated in 25% of the PMDS patients analyzed by Imbeaud et al. (1996). This deletion was present in the homozygous state in 4 patients and it was coupled with missense mutations in 6 patients.
Belville et al. (2009) investigated the effects of 4 AMHR2 mutations in the ECD and 6 mutations in the intracellular kinase domain (see, e.g., 600956.0002-600956.0004). Eight of the mutant receptors were still expressed at the cell surface. Two soluble receptors, truncated upstream of the transmembrane domain, were not secreted, unless the TGFBR2 (190182) signal sequence was substituted for the endogenous sequence. Belville et al. (2009) concluded that the AMHR2 signal sequence was defective in these mutants, and suggested that AMHR2 may use its transmembrane domain instead of its signal sequence to translocate to the endoplasmic reticulum (a characteristic of type III membrane proteins).
The type of persistent mullerian duct syndrome caused by mutation in the AMH gene will be referred to as type I; that form due to mutation in the AMH receptor (AMHR) will be designated type II.
Mishina et al. (1996) produced and examined AMHR2 knockout mice. They observed that mutant males were internal pseudohermaphrodites, having both male and female reproductive organs. The phenotype of AMH (600957)/AMHR2 double-knockout mutant males was indistinguishable from that of either single mutant. Furthermore, the phenotypes of AMH/alpha-inhibin and AMHR2/alpha-inhibin double-knockout mutant males were also identical, suggesting to the authors that AMH is the only ligand of the AMHR2 receptor.
Wang et al. (2009) presented evidence suggesting that AMH (MIS) is an important factor in the generation of variability of 'sex-linked bias,' or subtle behavioral differences between males and females. Most neurons in the adult mouse brain, spinal cord, and peripheral nervous system, as well as embryonic spinal cord motor neurons expressed the Amhr2 receptor. Only trace levels of Amh were detected in embryonic head, indicating that the prime embryonic source is from the testes. Male Amh-null or Amhr2-null mice showed subtle feminization of spinal cord motor neurons, i.e., fewer numbers of lumbar lateral motor neurons compared to wildtype males. However, androgen-dependent features were unaffected. Male Amhr2-null or Amh-null mice had partial feminization of exploratory behavior. Wang et al. (2009) suggested that Amh may be a regulator of neuronal pathways. The authors noted that Amh levels vary in the male population, which may underlie subtle sex-linked biases.
Imbeaud et al. (1995) demonstrated a G-to-A transition at position +1 of the splice donor site of intron 2 of the AMHR gene in a 3-month-old boy, born to allegedly unrelated Pakistani parents, who came to medical attention because of right cryptorchidism associated with a left inguinal hernia. At surgery, both testes were found in the left scrotum and inguinal canal, associated with a uterus and 2 fallopian tubes (see 261550). Biopsy showed normal seminiferous tubules containing germ cells. Normal regression of fetal rat mullerian ducts was elicited by coculture with a small testicular fragment, thus indicating that AMH was produced. Indeed, the AMH gene was sequenced and found to be normal in this patient. The G-to-A transition they found destroyed an HphI restriction site, allowing the determination of the genotype in the patient and his parents. The mutation was homozygous in the patient and both parents were heterozygotes. The mutation resulted in alternative splicing with production of 2 types of mRNA were produced: the shorter mRNA moiety showed skipping of the second exon with conservation of the reading frame; the longer one contained a 12-bp portion of intron 2, generated by the use of a cryptic donor sequence, GTATA, downstream of the splicing mutation. The result was a gly78-to-asp change of 1 amino acid followed by the insertion of 4 new residues, EWQR, at the end of exon 2.
Imbeaud et al. (1996) detected a 27-bp deletion (6331_6357del) in exon 10 of the AMHR gene, on at least 1 allele in 10 of 16 patients studied with AMHR mutations. The deletion was homozygous in 4 patients and was coupled with missense mutations in 6 patients.
Belville et al. (2009) noted that the 6331_6357del is missing residues 444 to 452, which are located at the top of the C-lobe in the X region of the kinase domain. Molecular modeling predicted that the deletion should lead to a substantial conformational change in the AMHR2 fold, since the residues constitute part of the alpha-G helix and the loop that precedes it.
In a family with 2 members with persistent mullerian duct syndrome (261550) and one normal sib, Messika-Zeitoun et al. (2001) detected 2 novel mutations of the AMHR2 gene. One, transmitted by the mother to her 3 sons, was a deletion of an adenosine at nucleotide position 1692 in exon 5, leading to a stop codon and causing receptor truncation after the transmembrane domain. The other, a missense mutation in the substrate-binding site of the kinase domain (600956.0004), was transmitted by the father to the 2 affected sons, indicating a recessive autosomal transmission as in other cases of persistent mullerian duct syndrome. Truncating mutations in receptors of the TGF-beta family exert dominant-negative activity, which was seen only when each of the mutant anti-mullerian hormone receptors was overexpressed in an anti-mullerian hormone-responsive cell line. The authors concluded that assessment of dominant activity in vitro, which usually involves overexpression of mutant genes, does not necessarily produce information applicable to clinical conditions, in which mutant and endogenous genes are expressed on a one-to-one basis.
Belville et al. (2009) noted that the 1692delA mutation lacks the entire kinase domain and is therefore incapable of transducing an AMH signal.
In the family with persistent mullerian duct syndrome (261550) reported by Messika-Zeitoun et al. (2001), the 2 affected sons were compound heterozygous for a G-to-A transition at nucleotide 6051 in exon 9 of the AMHR2 gene, causing replacement of an arginine by glutamine at codon 406 (R406Q). This mutation was transmitted by the father; the other mutation was a maternally transmitted 1-bp deletion (600956.0003).
Belville et al. (2009) noted that the R406Q mutation is located at the N terminus of the alpha-F helix, and molecular modeling predicted that substitution of the arg406 residues may destabilize the interaction between the alpha-E and alpha-F helices.
Belville, C., Marechal, J.-D., Pennetier, S., Carmillo, P., Masgrau, L., Messika-Zeitoun, L., Galey, J., Machado, G., Treton, D., Gonzales, J., Picard, J.-Y., Josso, N., Cate, R. L., di Clemente, N. Natural mutations of the anti-Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport. Hum. Molec. Genet. 18: 3002-3013, 2009. [PubMed: 19457927] [Full Text: https://doi.org/10.1093/hmg/ddp238]
Imbeaud, S., Belville, C., Messika-Zeitoun, L., Rey, R., di Clemente, N., Josso, N., Picard, J.-Y. A 27 base-pair deletion of the anti-mullerian type II receptor gene is the most common cause of the persistent mullerian duct syndrome. Hum. Molec. Genet. 5: 1269-1277, 1996. [PubMed: 8872466] [Full Text: https://doi.org/10.1093/hmg/5.9.1269]
Imbeaud, S., Faure, E., Lamarre, I., Mattei, M.-G., di Clemente, N., Tizard, R., Carre-Eusebe, D., Belville, C., Tragethon, L., Tonkin, C., Nelson, J., McAuliffe, M., Bidart, J.-M., Lababidi, A., Josso, N., Cate, R. L., Picard, J.-V. Insensitivity to anti-mullerian hormone due to a mutation in the human anti-mullerian hormone receptor. Nature Genet. 11: 382-388, 1995. [PubMed: 7493017] [Full Text: https://doi.org/10.1038/ng1295-382]
Kunieda, T., Ojika, I., Katoh, H. The gene encoding anti-mullerian hormone type 2 receptor maps to mouse chromosome 15. Mammalian Genome 9: 259-268, 1998. [PubMed: 9501316] [Full Text: https://doi.org/10.1007/s003359900739]
Messika-Zeitoun, L., Gouedard, L., Belville, C., Dutertre, M., Lins, L., Imbeaud, S., Hughes, I. A., Picard, J.-Y., Josso, N., di Clemente, N. Autosomal recessive segregation of a truncating mutation of anti-mullerian type II receptor in a family affected by the persistent mullerian duct syndrome contrasts with its dominant negative activity in vitro. J. Clin. Endocr. Metab. 86: 4390-4397, 2001. [PubMed: 11549681] [Full Text: https://doi.org/10.1210/jcem.86.9.7839]
Mishina, Y., Rey, R., Finegold, M. J., Matzuk, M. M., Josso, N., Cate, R. L., Behringer, R. R. Genetic analysis of the mullerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation. Genes Dev. 10: 2577-2587, 1996. [PubMed: 8895659] [Full Text: https://doi.org/10.1101/gad.10.20.2577]
Wang, P.-Y., Protheroe, A., Clarkson, A. N., Imhoff, F., Koishi, K., McLennan, I. S. Mullerian inhibiting substance contributes to sex-linked biases in the brain and behavior. Proc. Nat. Acad. Sci. 106: 7203-7208, 2009. [PubMed: 19359476] [Full Text: https://doi.org/10.1073/pnas.0902253106]