|
Comment |
The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome. Li M et al. (2018) The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study (GWAS) as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. mRNA expression in ovarian GCs was measured using qRT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. HMGA2 and IMP2 were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. CCND2 (Cyclin D2) and SERBP1 (SERPINE1 mRNA binding protein 1) were regulated by IMP2 and were highly expressed in women with PCOS. The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.//////////////////
Expression of HMGA2 variants during oogenesis and early embryogenesis of Xenopus laevis. Hock R et al. The high mobility group proteins A2 (HMGA2) have been implicated in the control of cell proliferation and differentiation, in particular during embryogenesis. Here, we used Xenopus laevis to analyze HMGA2 gene expression patterns during oogenesis and early embryogenesis. We found two functional XlHMGA2 isoforms, which we named XlHMGA2alpha and XlHMGA2beta. As revealed by RT-PCR, real-time PCR and whole-mount in situ hybridization both mRNAs are maternally produced and stored in eggs. Whole-mount in situ hybridizations revealed a conspicuous redistribution of the XlHMGA2 transcripts during early embryogenesis. Initially, during oogenesis and in eggs, the transcripts are uniformly distributed in the cytoplasm. With activation of the eggs the transcripts accumulate near the animal pole and remain in the juxtanuclear regions of animal pole blastomeres until midblastula transition. According to real-time PCR data, XlHMGA2alpha appears to be preferentially expressed during oogenesis and after midblastula transition, whereas XlHMGA2beta expression predominates after neurulation, suggesting an individual transcriptional regulation.
|
|
Comment |
Expression goes down during oocyte development./////Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Gallardo TD et al. Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility. This is an oocyte-specific gene.
HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma. Mahajan A et al. Ovarian carcinoma consists of a group of histologically heterogeneous diseases involving distinct tumorigenic pathways. High-grade papillary serous carcinoma of the ovary is commonly associated with p53 mutations. HMGA2, an oncofetal protein, is found to be overexpressed in ovarian cancer. To study the function of HMGA2 in ovarian cancer, it is important to know which subtypes of ovarian cancer are associated with HMGA2 overexpression. In this study, we collected six different types of ovarian cancer and examined HMGA2 expression by immunohistochemistry, along with HMGA1, p53 and Ki-67. We found that HMGA2 overexpression was significantly higher in high-grade papillary serous carcinoma (64%) and carcinosarcoma (60%) than in other types of ovarian cancers (7-23%). HMGA2 overexpression was moderately associated with dominant p53 mutations (R=0.51). In addition, the microRNA in situ analysis revealed that let-7b, the HMGA2-negative regulators, were significantly lost in high-grade serous carcinoma. Our findings suggest that HMGA2 is an important molecular change significantly related to high-grade papillary serous carcinoma and is less common in other histological types of ovarian cancer.Modern Pathology advance online publication, 12 March 2010; doi:10.1038/modpathol.2010.49.
|
|
Mutations |
3 mutations
Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Shi Y et al. Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 ?10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.
Species: mouse
Mutation name: None
type: null mutation
fertility: None
Comment: Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Zhou X et al. Growth is one of the fundamental aspects in the development of an organism. Classical genetic studies have isolated four viable, spontaneous mouse mutants disrupted in growth, leading to dwarfism. Pygmy is unique among these mutants because its phenotype cannot be explained by aberrations in the growth hormone-insulin-like growth factor endocrine pathway. Here we show that the pygmy phenotype arises from the inactivation of Hmgi-c (ref. 6), a member of the Hmgi family which function as architectural factors in the nuclear scaffold and are critical in the assembly of stereospecific transcriptional complexes. Hmgi-c and another Hmgi family member, Hmgi(gamma) (ref. 10), were found to be expressed predominantly during embryogenesis. The HMGI proteins are known to be regulated by cell cycle-dependent phosphorylation which alters their DNA binding affinity. These results demonstrate the important role of HMGI proteins in mammalian growth and development.
Species: porcine
Mutation name:
type: null mutation
fertility: None
Comment: High mobility group A2 (HMGA2) deficiency in pigs leads to dwarfism, abnormal fetal resource allocation, and cryptorchidism. Chung J et al. (2018) Expression of HMGA2 is strongly associated with body size and growth in mice and humans. In mice, inactivation of one or both alleles of Hmga2 results in body-size reductions of 20% and 60%, respectively. In humans, microdeletions involving the HMGA2 locus result in short stature, suggesting the function of the HMGA2 protein is conserved among mammals. To test this hypothesis, we generated HMGA2-deficient pigs via gene editing and somatic cell nuclear transfer (SCNT). Examination of growth parameters revealed that HMGA2-/+ male and female pigs were on average 20% lighter and smaller than HMGA2+/+ matched controls (P < 0.05). HMGA2-/- boars showed significant size reduction ranging from 35 to 85% of controls depending on age (P < 0.05), and organ weights were also affected (P < 0.05). HMGA2-/+ gilts and boars exhibited normal reproductive development and fertility, while HMGA2-/- boars were sterile due to undescended testes (cryptorchidism). Crossbreeding HMGA2-/+ boars and gilts produced litters lacking the HMGA2-/- genotype. However, analysis of day (D) D40 and D78 pregnancies indicated that HMGA2-/- fetuses were present at the expected Mendelian ratio, but placental abnormalities were seen in the D78 HMGA2-/- concepti. Additionally, HMGA2-/- embryos generated by gene editing and SCNT produced multiple pregnancies and viable offspring, indicating that lack of HMGA2 is not lethal per se. Overall, our results show that the effect of HMGA2 with respect to growth regulation is highly conserved among mammals and opens up the possibility of regulating body and organ size in a variety of mammalian species including food and companion animals.//////////////////
|