NCBI Summary:
CD222 is a 250kDa transmembrane protein with a short cytoplasmic tail containing an internalization signal. CD222 was originally identified as a receptor for IGFII and M6P-containing proteins (e.g. lysosomal hydrolases). Lysosomal enzymes are sorted to lysosomes via CD222 either from the Golgi, where the enzymes acquire M6P, or from the extracellular space. The majority of CD222 molecules (approximately 90-95%) are located intracellularly, only 5-10% is present on the cell membrane. The internalization rate seems to be enhanced by ligand induced dimerization of CD222 as well as by phosphorylation of its cytoplasmic serine. CD222 is also a receptor for TGFbeta latency associated peptide (LAP), proliferin and may bind several molecules independently of M6P, including plasminogen, CD87 or retinoic acid. It is involved in activation of latent TGFbeta [PROW]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Early embryo development
Comment
Possible role of IGF2 receptors in regulating selection of 2 dominant follicles in cattle selected for twin ovulations and births. Aad PY 2013 et al.
Abundance of IGF-2 receptor (IGF2R), FSH receptor (FSHR), and LH receptor (LHCGR) mRNA in granulosa cells (GCs) or theca cells (TCs) or both cells as well as estradiol (E2), progesterone (P4), and androstenedione concentrations in follicular fluid were compared in cows genetically selected (Twinner) or not selected (control) for multiple ovulations and twin births. Cows were slaughtered at day 3 to 4 (day 3) and day 5 to 6 (day 5) of an estrous cycle, and ovaries, follicular fluid, GCs, and TCs were collected. The two largest (F1 and F2) E2-active (EA) and E2-inactive (EI) follicles were selected according to their E2-to-P4 ratio and diameter. Androstenedione levels in EA F1 and F2 follicles were 5-fold greater (P < 0.05) in Twinner cows than in control cows on day 3 but did not differ on day 5. Twinner cows also had greater (P < 0.05) E2 and P4 concentrations, whereas steroid levels in EI follicles did not differ (P > 0.10) between genotypes. In EA F2 follicles, IGF2R levels in GCs were greater (P < 0.05) in control cows than in Twinner cows on day 3 and day 5, whereas IGF2R mRNA in TCs did not differ (P > 0.10). On day 3, FSHR mRNA levels were greater (P < 0.05) in GCs of EA F1 and EI F2 follicles of control cows than of Twinner cows. LH receptor mRNA expression was less in GCs and greater in TCs of EA F2 follicles in control cows than in Twinner cows (P < 0.05). We hypothesize that reduced GC IGF2R expression in F2 follicles of Twinner cows may play a role in the development of 2 or more dominant follicles.
/////////////////////////
Effects of Low Methyl Donor Levels in Culture Medium During Mouse Follicle Culture on Oocyte Imprinting Establishment. Anckaert E et al. Imprinted genes are differentially methylated during gametogenesis to allow parent-of-origin specific monoallelic expression. We previously demonstrated normal imprinting establishment at four key imprinted genes in mouse MII oocytes after in vitro follicle culture. Commercially available culture media feature a wide range of methyl donor levels. The aim was to study the effect of low methyl donor (methionine, vitamin B12, folic acid, choline and vitamin B6) levels during follicle culture on DNA methylation acquisition at imprinted genes in mouse oocytes. Follicle culture performed under low methyl donor levels led to decreased antral follicle development: mean (SD) antral follicle rate was 87.5 (12.6)% versus 97.7 (4.3)% in control conditions, P < 0.05; and to a dramatic decrease in polar body (PB) oocyte rate: mean (SD) PB oocyte rate was 38.7 (25.5)% versus 96.1 (7.1)%; P < 0.001. The methylation status of differentially methylated regions (DMRs) of 4 key imprinted genes was studied (by bisulphite sequencing) in normal-looking PB and GVBD-arrested oocytes obtained from follicle culture under low methyl donor levels. DMRs of Snrpn, Igf2r, and H19 showed no alteration in DNA methylation, but at Mest DMR in PB oocytes we found a significant reduction in DNA methylation compared to control follicle culture (% DNA methylation was respectively 89.9% and 98.2%, P = 0.0014). In conclusion, restriction of methyl donors during follicle culture led to a dramatic decrease in PB oocyte rate, but induced no or only minor DNA methylation alterations at the studied regulatory sequences of key imprinted genes in oocytes.
Expression regulated by
Comment
Germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation. Cheong CY et al. (2015) Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline-derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These suggest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted domains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease.//////////////////
Ovarian localization
Granulosa, Theca
Comment
el-Roeiy A, et al. examined the expression of the genes encoding the IGFs, IGF receptors (IGFr), insulin receptor (Ir), and IGF-binding proteins (IGFBPs-1-6) as well as the localization of the gene products in specific cellular compartments of normal and PCOS human ovaries. Messenger ribonucleic acid (mRNA) was localized by in situ hybridization with specific 35S-labeled human antisense RNA probes, and protein was detected by immunohistochemistry using specific antisera. Thecal cells, but not granulosa cells (GC), of small antral follicles (3-6 mm) from PCOS ovaries expressed both IGF-I and IGF-II transcripts. Abundant IGF-Ir mRNA was found only in GC, IGF-IIr mRNA was found in both granulosa and thecal cells, and Ir mRNA was detected in all cell types, including granulosa, thecal, and stromal cells. Localization of the gene products revealed no IGF-I immunoreactivity; however, immunostaining for each of the other gene products was colocalized with its corresponding mRNA. The cellular distribution of mRNA and protein in PCOS follicles was indistinguishable from that observed in small antral follicles from normal ovaries. In dominant follicles, however, IGF-I mRNA was no longer detectable, but abundant IGF-II mRNA was expressed exclusively in GC. Although IGF-Ir mRNA was expressed in GC, IGF-IIr mRNA was found in both granulosa and thecal cells. In follicles taken from PCOS ovaries, no IGFBP-1 mRNA was detected, IGFBP-2 mRNA was abundant in both granulosa and thecal cells, moderate IGFBP-3 mRNA was found only in thecal cells, IGFBP-4 and -5 mRNAs were present in all cellular compartments, and IGFBP-6 mRNA was not detected. Localization of the gene products by immunostaining revealed that each protein colocalized with its corresponding mRNA. This gene was also found through a mouse ovarian follicle microarray.
Follicle stages
Comment
Phenotypes
POF (premature ovarian failure)
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure. Pyun JA 2013 et al.
STUDY QUESTION
Do single nucleotide polymorphisms (SNPs) or synergistic interactions between SNPs and diplotypes within the insulin-like growth factor 2 receptor (IGF2R) and ADAM metallopeptidase with thrombospondin type 1 motif, 19 (ADAMTS19), contribute to premature ovarian failure (POF)?
SUMMARY ANSWER
Synergistic interactions were detected between SNPs, including a non-synonymous SNP, and diplotypes within IGF2R and ADAMTS19 which may contribute to POF; however, there was no correlation with POF in a single SNP model after Bonferroni correction.
WHAT IS KNOWN ALREADY
IGF2R regulates free IGF2 level, which is involved in steroidogenesis in bovine granulosa cells. ADAMTS19 expression is higher in the murine embryonic ovary than in the embryonic testis during sexual differentiation, and an ADAMTS19 SNP (rs246246) showed a possible association with POF in a genome-wide association study in Caucasian women.
STUDY DESIGN, SIZE, DURATION
This study analyzed interactions between SNPs and diplotypes within IGF2R and ADAMTS19 as well as SNPs within the two genes. In Stage I, a total of 120 patients with POF and 152 female controls were recruited. All patients were diagnosed with POF at the CHA hospital in Seoul, Korea, and were recruited between 1994 and 2004. The 152 controls were recruited from Chungju, Korea, as part of another study that was conducted from April 2002 to March 2004. For Stage II, we obtained genotype data for an additional 1641 female controls, recruited in Ansung and Ansan from 2001 to 2008, from the Korean Genome Epidemiology Study (KoGES).
PARTICIPANTS/MATERIALS, SETTING, METHODS
In Stage I, the GoldenGate assay with VeraCode technology was used to genotype SNPs in IGF2R and ADAMTS19. In Stage II, we obtained genotype data for IGF2R and ADAMTS19 using Affymetrix Genome-Wide Human SNP array 5.0 and imputed data by the IMPUTE program from the KoGES. To identify POF-associated SNPs, logistic regression analysis in an additive model was performed using the PLINK tool. Synergistic interactions between SNPs and diplotypes within IGF2R and ADAMTS19 were analyzed by logistic regression analysis in three alternative models.
MAIN RESULTS AND THE ROLE OF CHANCE
In Stage I, 13 combinations of SNPs showed significant synergistic interactions after Bonferroni correction [the strongest association had odds ratio (OR) = 5.77, 95% confidence interval (CI): 2.26-14.75, P = 0.00025]. In Stage II and combined analyses, two and four combinations, respectively, of the significant results in Stage I showed significant synergistic interactions after Bonferroni correction. For interactions between diplotypes in block 2 of IGF2R and block 3 of ADAMTS19 in Stage I, we found 17 synergistic interactions with P < 0.0001, but there was no significant interaction after Bonferroni correction. In Stage II and combined analyses, we found that three and seven combinations in the same blocks, respectively, showed significant synergistic interactions after Bonferroni correction (strongest association: OR = 4.12, 95% CI: 2.22-7.62, P = 6.74E-06).
LIMITATIONS, REASONS FOR CAUTION
The sample size for patients with POF in this study was small but, compared with recent reports describing associations between SNPs and POF and considering the low prevalence of POF (1%), the sample size is considered to be reasonable. These results should be confirmed in large-scale studies involving different ethnic groups.
WIDER IMPLICATIONS OF THE FINDINGS
Our results may ultimately provide predictive markers for women at a high risk of POF.
STUDY FUNDING/COMPETING INTERESTS
This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2009-0093821, 2011-0010637). There are no competing interests.
/////////////////////////