AMHR2
Anti-Muellerian hormone type-2 receptor precursor (EC 2.7.11.30) (Anti-Muellerian hormone type II receptor) (AMH type II receptor) (MIS type II receptor) (MISRII) (MRII) [AMHR] [MISR2]
Publications[править]
Cow fertility decreases with age, but the hypothalamic pathomechanisms are not understood. Anti-Müllerian hormone (AMH) stimulates gonadotropin-releasing hormone (GnRH) neurons via AMH receptor type 2 ([[AMHR2]]), and most GnRH neurons in the preoptic area (POA), arcuate nucleus (ARC), and median eminence (ME) express AMH and [[AMHR2]]. Therefore, we hypothesized that both protein amounts would differ in the anterior hypothalamus (containing the POA) and posterior hypothalamus (containing the ARC and ME) between young post-pubertal heifers and old cows. Western blot analysis showed lower (P<0.05) expressions of AMH and [[AMHR2]] in the posterior hypothalamus, but not in the anterior hypothalamus, of old Japanese Black cows compared to young heifers. Therefore, AMH and [[AMHR2]] were decreased in the posterior hypothalami of old cows.
Keywords
- Müllerian inhibiting substance
- female reproductive senescence
- gonadotropin-releasing hormone neuron
- preoptic area
- ruminant
The genetics of lifespan determination is poorly understood. Most research has been done on short-lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. To gain new insights into genetic mechanisms determining mammalian lifespans, we obtained genomic and transcriptomic data from 17 rodent species and scanned eleven evolutionary branches associated with the evolution of enhanced longevity for positively selected genes (PSGs). Indicating relevance for aging, the set of 250 identified PSGs showed in liver of long-lived naked mole-rats and short-lived rats an expression pattern that fits the antagonistic pleiotropy theory of aging. Moreover, we found the PSGs to be enriched for genes known to be related to aging. Among these enrichments were "cellular respiration" and "metal ion homeostasis", as well as functional terms associated with processes regulated by the mTOR pathway: translation, autophagy and inflammation. Remarkably, among PSGs are RHEB, a regulator of mTOR, and IGF1, both central components of aging-relevant pathways, as well as genes yet unknown to be aging-associated but representing convincing functional candidates, e.g. RHEBL1, AMHR2, PSMG1 and AGER. Exemplary protein homology modeling suggests functional consequences for amino acid changes under positive selection. Therefore, we conclude that our results provide a meaningful resource for follow-up studies to mechanistically link identified genes and amino acids under positive selection to aging and lifespan determination.
MeSH Terms
- Animals
- Genome
- Homeostasis
- Ion Transport
- Longevity
- Oxidative Stress
- Rodentia
- Selection, Genetic
- Species Specificity
- Transcriptome
The onset of menopause has important implications on women's fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, [[AMHR2]], BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in [[AMHR2]] (p = 0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary.
MeSH Terms
- Age Factors
- Aging
- Anti-Mullerian Hormone
- Epistasis, Genetic
- Female
- Humans
- Menopause
- Middle Aged
- Ovarian Follicle
- Polymorphism, Single Nucleotide
- Receptors, Peptide
- Receptors, Transforming Growth Factor beta
Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conserved in long-lived but not short-lived mammal species. We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and a homology model of the kinase domain shows that its longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein's activity in a lifespan-specific manner.
MeSH Terms
- Age Factors
- Animals
- Cluster Analysis
- Conserved Sequence
- Evolution, Molecular
- Humans
- Linear Models
- Longevity
- Mammals
- Models, Genetic
- Mutation Rate
- Protein Structure, Tertiary
- Proteome
- Proteomics
- Receptors, Peptide
- Receptors, Transforming Growth Factor beta
- Selection, Genetic
- Species Specificity
Timing of menopause is largely influenced by genetic factors. Because menopause occurs when the follicle pool in the ovaries has become exhausted, genes involved in primordial follicle recruitment can be considered as candidate genes for timing of menopause. The aim was to study the association of 23 tagging single nucleotide polymorphisms in five genes [Anti-Müllerian hormone (AMH), AMH type II receptor ([[AMHR2]]), bone morphogenetic protein 15 (BMP15), forkhead transcription factor L2 (FOXL2), and growth differentiation factor-9 (GDF9)] involved in recruitment of the primary follicle pool, including the [[AMHR2]] gene, which has recently been associated with age at menopause. We conducted a cross-sectional association study. We studied a population-based sample of 3616 Dutch women with natural menopause. We measured age at natural menopause. Both studied [[AMHR2]] tagging single nucleotide polymorphisms (rs2002555 and rs11170547) in the [[AMHR2]] gene were associated with age at natural menopause in interaction with parity. Parous rs2002555 G/G carriers had menopause 1 yr later compared with A/A carriers (P = 0.01). For rs11170547, each minor allele (T) was associated with a 0.41-yr later onset of menopause in parous women (P = 0.01). Additionally, rs6521896 in BMP15 was associated with later menopause (β = 0.41; P = 0.007). Variants in the AMH, FOXL2, and GDF9 genes were not associated with timing of menopause. The present study confirms an earlier finding that variation in the [[AMHR2]] gene modifies the relation between parity and age at natural menopause. In combination with the association of BMP15 with menopausal age, we find that there is evidence that genes involved in primary follicle recruitment influence timing of menopause.
MeSH Terms
- Aged
- Aging
- Alleles
- Anti-Mullerian Hormone
- Bone Morphogenetic Protein 15
- Cohort Studies
- Cross-Sectional Studies
- Female
- Forkhead Box Protein L2
- Forkhead Transcription Factors
- Genotype
- Growth Differentiation Factor 9
- Humans
- Menopause
- Middle Aged
- Netherlands
- Ovarian Follicle
- Parity
- Polymorphism, Single Nucleotide
- Postmenopause
- Receptors, Peptide
- Receptors, Transforming Growth Factor beta