Alternative titles; symbols
HGNC Approved Gene Symbol: AMH
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:2,249,323-2,252,073 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Persistent Mullerian duct syndrome, type I | 261550 | Autosomal recessive | 3 |
Male sex differentiation is mediated by 2 discrete hormones produced by the fetal testis. Testosterone, produced by Leydig cells, virilizes the external genitalia and promotes prostatic growth; anti-mullerian hormone (AMH), also called mullerian-inhibiting substance (MIS) or factor (MIF), results in regression of mullerian ducts which would otherwise differentiate into the uterus and fallopian tubes.
Picard et al. (1986) used mRNA prepared from fetal bovine testicular tissue to construct a cDNA library. They isolated cDNAs encoding a fragment of bovine AMH and showed by Northern blots that the gene was expressed only in fetal testis and adult ovarian follicles.
Cate et al. (1986) isolated the human gene for MIF. The gene encodes a 560-amino acid polypeptide. The highly conserved C-terminal domain of the protein shows marked homology with human transforming growth factor-beta (190180) and the beta chain of porcine inhibin (147390).
Lee et al. (1997) demonstrated that measurements of serum mullerian-inhibiting substance can be used to determine testicular status in prepubertal children with nonpalpable gonads, thus differentiating anorchia from undescended testes in boys with bilateral cryptorchidism and serving as a measure of testicular integrity in children with intersexual anomalies.
To determine the value of assessing serum AMH levels in the diagnosis of intersex conditions, Rey et al. (1999) assayed levels in 107 patients with ambiguous genitalia of various etiologies. In XY patients, AMH was low when the intersex condition was caused by abnormal testicular determination (including pure and partial gonadal dysgenesis) but was normal or elevated in patients with impaired testosterone secretion, whereas serum testosterone was low in both groups. AMH was also elevated during the first year of life and at puberty in intersex states caused by androgen insensitivity. In 46,XX patients with a normal male phenotype or ambiguous genitalia in whom the diagnosis of female pseudohermaphroditism had been excluded, AMH levels greater than 75 pmol/L were indicative of the presence of testicular tissue and correlated with the mass of functional testicular parenchyma. The authors concluded that serum AMH determination is a powerful tool to assess Sertoli cell function in children with intersex states that can help to distinguish between defects of male sexual differentiation caused by abnormal testicular determination and those resulting from isolated impairment of testosterone secretion or action.
Misra et al. (2003) examined the role of MIS determination in the evaluation of 65 phenotypic females with mild virilization. Among the 28 subjects with MIS values above the normal female range, all had abnormal gonadal tissue: ovotestes in 11, testes in 7, dysgenetic gonads in 7, and MIS-secreting ovarian tumors in 3. Among the 37 children with serum MIS in the normal female range, 19 had detectable MIS and 18 had unmeasurable MIS. In the former group with measurable but normal female MIS values, 16 subjects had ovaries, 1 had an ovotestis, and 1 had dysgenetic gonads containing testicular elements. Of 18 children with undetectable MIS values, 16 had ovaries and 2 had ovarian dysgenesis. The authors concluded that elevation of serum MIS above the normal female range was consistently associated with the presence of testicular tissue or MIS-secreting tumors, mandating additional evaluation and surgical exploration.
To investigate the correlation between AMH levels and age of onset of menopause, van Disseldorp et al. (2008) measured AMH levels in 144 fertile normal volunteers and determined the mean AMH as a function of age. The authors found good conformity between the observed distribution of age at menopause and that predicted from declining AMH levels. Van Disseldorp et al. (2008) concluded that the similarity between observed and predictive distributions of age at menopause supported the hypothesis that AMH levels are related to onset of menopause.
Forest (1997) commented that there is no evidence of any biologic action of mullerian-inhibiting substance after birth. Its overproduction in patients with sex-cord tumors does not seem to have any harmful effects.
Wang et al. (2005) found that motor neurons of adult male and female mice synthesized Mis and expressed its receptors. Mis supported survival of embryonic motor neurons in vitro at physiologic concentrations, suggesting that mature motor neurons use MIS for communication or as an autocrine factor. Wang et al. (2005) postulated that MIS may have a hormone effect in developing males due to the delayed development of the blood-brain barrier, possibly resulting in sex-specific differences in motor neurons.
Anttonen et al. (2005) studied the role of factors regulating normal granulosa cell function, i.e., AMH, inhibin-alpha (147380), steroidogenic factor-1 (SF1; 184757), and GATA transcription factors (e.g., GATA4, 600576) in the pathobiology and clinical behavior of granulosa cell tumors (GCTs). The more aggressive GCTs retained a high GATA4 expression, whereas the larger tumors lost the proliferation-suppressing AMH expression. Anttonen et al. (2005) concluded that the high GATA4 expression in GCTs may serve as a marker of poor prognosis.
Cate et al. (1986) determined that the human MIF gene has 5 exons.
Cohen-Haguenauer et al. (1987) mapped the gene for AMH to 19p13.3-p13.2, using in situ hybridization and Southern blot analysis of a panel of human-mouse and human-hamster somatic cell hybrids.
By study of cow-hamster and cow-mouse somatic cell hybrids, Rogers et al. (1991) showed that the AMH and SPARC (182120) genes are syntenic in cattle. SPARC maps to chromosome 5 in the human.
By linkage mapping, King et al. (1991) demonstrated that the Amh gene is on mouse chromosome 10. This analysis identified a new region of linkage homology between human 19p and mouse 10.
Knebelmann et al. (1991) demonstrated a missense mutation in the AMH gene in a patient with AMH-negative persistent mullerian duct syndrome (see 600957.0001).
Imbeaud et al. (1994) performed molecular analysis of the AMH gene in 21 patients with persistent mullerian duct syndrome (PMDS; 261550) and their families. In 6 patients with normal serum concentration of AMH, the AMH was normal or contained only polymorphisms and silent mutations, supporting the hypothesis that the condition is due to end-organ resistance. In the 15 remaining patients with low or undetectable levels of serum AMH, 9 novel mutations were discovered. When present in homozygotes or compound heterozygotes, these mutations were associated with the PMDS phenotype, the same mutation never being observed in 2 different families. The first 3 exons of the AMH gene appeared particularly mutation-prone, although they are less GC rich than the 2 last exons and code for the N-terminal part of the AMH protein, which is not in itself essential to bioactivity.
Guerrier et al. (1989) demonstrated that not all cases of PMDS are caused by a defect of the AMH gene itself; some patients express a normal amount of bioactive testicular AMH. PMDS, 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 and sometimes due to mutations in AMHR (600956), the AMH receptor gene (Imbeaud et al., 1995). These 2 forms of persistent mullerian duct syndrome are referred to as types 1 and 2, respectively.
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 AMH receptor mutations in 32 families. Six of the patients were postpubertal, and in these patients determination of the level of anti-mullerian hormone was no longer informative, since AMH production is normally repressed after puberty. In prepubertal patients, 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 mutations were extremely diverse, and were identified in 16 families, including 9 previously reported families (Imbeaud et al., 1994). Imbeaud et al. (1996) reported that exon 1 and the 3-prime half of exon 5 of the AMH gene are the main sites of deleterious changes including short deletions and missense mutations.
To investigate the role of the AMH signaling pathway in the pathophysiology of polycystic ovary syndrome (PCOS; see 184700), Kevenaar et al. (2008) studied the association of the AMH I49S and the AMHR -482A-G polymorphisms with PCOS susceptibility and phenotype in 331 women with PCOS and 32 normoovulatory controls, all Dutch Caucasians. Allele and genotype frequency of these polymorphisms in the Dutch Caucasian population were determined using 3,635 population-based controls. Kevenaar et al. (2008) found that genotype and allele frequencies for the 2 polymorphisms were similar in PCOS women and controls. However, within the group of PCOS women, carriers of the AMH 49S allele had polycystic ovaries less often (92.7 vs 99.5%, p = 0.0004), lower follicle numbers (p = 0.03), and lower androgen levels, compared with noncarriers (p = 0.04). In addition, in vitro studies demonstrated that the bioactivity of the AMH 49S protein is diminished compared with the AMH 49I protein (p less than 0.0001). Kevenaar et al. (2008) concluded that whereas these genetic variants do not influence PCOS susceptibility, the AMH I49S polymorphism contributes to the severity of the PCOS phenotype.
Mishina et al. (1996) produced and examined AMHR2 (600956) knockout mice. They observed that mutant males were internal pseudohermaphrodites, having both male and female reproductive organs. The phenotype of AMH/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.
Arango et al. (1999) introduced mutations into conserved Sf1 (184757)- and Sox9 (608160)-binding sites within the endogenous mouse Mis promoter. Male mice homozygous for the mutant Sf1-binding site correctly initiated Mis transcription in fetal testes, although at significantly reduced levels. Surprisingly, sufficient Mis was produced to eliminate the mullerian ducts. In contrast, males homozygous for the mutant Sox9-binding site did not initiate Mis transcription, resulting in pseudohermaphrodites. These studies suggested an essential role for SOX9 in the initiation of MIS transcription, whereas SF1 appeared to act as a quantitative regulator of MIS transcript levels, perhaps for influencing non-mullerian duct tissues. Comparative studies of MIS expression in vertebrates indicated that the MIS promoter receives transcriptional inputs that vary between species but result in the same functional readout.
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.
Because MIF is also used as the symbol for macrophage migration inhibitory factor (153620), AMH, for anti-mullerian hormone, will be considered the preferred symbol for the locus on chromosome 19.
In 3 brothers of Moroccan ancestry previously reported by Guerrier et al. (1989) as having an AMH-negative form of PMDS (261550), Knebelmann et al. (1991) identified a point mutation in the AMH gene: a 2096G-T transversion in the fifth exon, changing codon GAA (glu) at position 358 to TAA (stop) (E358X). This variant has been designated anti-mullerian hormone Bruxelles.
Carre-Eusebe et al. (1992) found 2 mutations in the AMH gene in the 3-month-old patient with PMDS (261550) reported by Harbison et al. (1991). The child was born to healthy unrelated New York parents of Italian descent. A right inguinal hernia was noted at the age of 1 month. Surgery on the 79th day of life revealed that both gonads were within the right hernia sac. Attached to each gonad was an unremarkable epididymis, vas deferens, and fallopian tube. Between the fallopian tubes was what appeared to be an infantile uterus. No serum anti-mullerian hormone could be detected by enzyme-linked immunosorbent assay. Sequencing of cloned PCR-amplified fragments of the AMH gene revealed a 14-bp deletion in the second exon of the maternal allele; this deletion disrupted the open reading frame. Nucleotides 1074-1087 were deleted at a site containing two 8-bp direct repeats flanking a 6-bp sequence; the deletion removed one whole repeat plus all of the intervening sequence. The deletion had resulted from slipped mispairing at the DNA replication fork. The paternal allele contained an arg191-to-ter mutation due to a C-to-T transition at nucleotide 1345 changing CGA to UGA and leading to the synthesis of a truncated protein of 190 amino acid residues. A phenotypically normal younger sister had the same 2 mutant alleles. In this family various other mutations of the AMH gene, devoid of physiologic significance, were found, suggesting that the AMH gene is highly polymorphic.
See 600957.0002 and Carre-Eusebe et al. (1992).
In brothers with bilateral cryptorchidism shown to have persistent mullerian duct syndrome (261550), Lang-Muritano et al. (2001) identified homozygosity for a 23-bp duplication in exon 5 of the AMH gene, beginning at nucleotide 2349. Each parent was heterozygous for the mutation.
Anttonen, M., Unkila-Kallio, L., Leminen, A., Butzow, R., Heikinheimo, M. High GATA-4 expression associates with aggressive behavior, whereas low anti-mullerian hormone expression associates with growth potential of ovarian granulosa cell tumors. J. Clin. Endocr. Metab. 90: 6529-6535, 2005. [PubMed: 16159935] [Full Text: https://doi.org/10.1210/jc.2005-0921]
Arango, N. A., Lovell-Badge, R., Behringer, R. R. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell 99: 409-419, 1999. [PubMed: 10571183] [Full Text: https://doi.org/10.1016/s0092-8674(00)81527-5]
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King, T. R., Lee, B. K., Behringer, R. R., Eicher, E. M. Mapping anti-mullerian hormone (Amh) and related sequences in the mouse: identification of a new region of homology between MMU10 and HSA19p. Genomics 11: 273-283, 1991. [PubMed: 1685136] [Full Text: https://doi.org/10.1016/0888-7543(91)90133-y]
Knebelmann, B., Boussin, L., Guerrier, D., Legeai, L., Kahn, A., Josso, N., Picard, J.-Y. Anti-mullerian hormone Bruxelles: a nonsense mutation associated with the persistent mullerian duct syndrome. Proc. Nat. Acad. Sci. 88: 3767-3771, 1991. [PubMed: 2023927] [Full Text: https://doi.org/10.1073/pnas.88.9.3767]
Lang-Muritano, M., Biason-Lauber, A., Gitzelmann, C., Belville, C., Picard, Y., Schoenle, E. J. A novel mutation in the anti-mullerian hormone gene as cause of persistent mullerian duct syndrome. Europ. J. Pediat. 160: 652-654, 2001. [PubMed: 11760020] [Full Text: https://doi.org/10.1007/s004310100840]
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Misra, M., MacLaughlin, D. T., Donahoe, P. K., Lee, M. M. The role of mullerian inhibiting substance in the evaluation of phenotypic female patients with mild degrees of virilization. J. Clin. Endocr. Metab. 88: 787-792, 2003. [PubMed: 12574214] [Full Text: https://doi.org/10.1210/jc.2002-020889]
Picard, J.-Y., Benarous, R., Guerrier, D., Josso, N., Kahn, A. Cloning and expression of cDNA for anti-mullerian hormone. Proc. Nat. Acad. Sci. 83: 5464-5468, 1986. [PubMed: 2426698] [Full Text: https://doi.org/10.1073/pnas.83.15.5464]
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Rogers, D. S., Gallagher, D. S., Womack, J. E. Somatic cell mapping of the genes for anti-mullerian hormone and osteonectin in cattle: identification of a new bovine syntenic group. Genomics 9: 298-300, 1991. [PubMed: 2004779] [Full Text: https://doi.org/10.1016/0888-7543(91)90256-e]
van Disseldorp, J., Faddy, M. J., Themmen, A. P. N., de Jong, F. H., Peeters, P. H. M., van der Schouw, Y. T., Broekmans, F. J. M. Relationship of serum antimullerian hormone concentration to age at menopause. J. Clin. Endocr. Metab. 93: 2129-2134, 2008. [PubMed: 18334591] [Full Text: https://doi.org/10.1210/jc.2007-2093]
Wang, P.-Y., Koishi, K., McGeachie, A. B., Kimber, M., MacLaughlin, D. T., Donahoe, P. K., McLennan, I. S. mullerian Inhibiting Substance acts as a motor neuron survival factor in vitro. Proc. Nat. Acad. Sci. 102: 16421-16425, 2005. [PubMed: 16260730] [Full Text: https://doi.org/10.1073/pnas.0508304102]
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]