{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent genetic mapping has implicated the fibrillin‐3 (FBN3) gene in polycystic ovary syndrome (PCOS), with linkage of markers in intron 55 (D19S884) suggesting a role in ovarian pathophysiology and endocrine regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, investigations into FBN3 polymorphisms have extended to disorders of abnormal skeletal growth, such as adolescent idiopathic scoliosis, indicating that genetic variation in FBN3 may influence overall growth patterns."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Detailed single nucleotide polymorphism analyses in PCOS cohorts have shown that although FBN3 messenger RNA levels are considerably lower than those of related fibrillin proteins in adult ovarian tissue, specific alleles (e.g., the D19S884 A8 allele) are associated with altered circulating transforming growth factor‐β (TGF‐β) isoforms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Immunohistochemical studies further demonstrate that fibrillin‐3 localizes to a restricted domain within the specialized perifollicular stroma of transitional follicles—suggesting a role in the primordial to primary follicle transition—and that its reduced presence is a common feature in polycystic ovaries."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDuring early human development, FBN3 is temporally expressed in multiple tissues—including perichondrium, skin, and developing bronchi—implying both overlapping and distinct roles compared with other fibrillin family members."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the fetal ovary, the dynamic expression of fibrillin‐3 in stromal compartments coincides with critical stages of follicle formation and appears to influence TGF‐β bioavailability, a pathway that may predispose to the PCOS phenotype later in life."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, genetic studies in women with PCOS have linked FBN3 risk variants to metabolic alterations—including perturbed insulin secretion and endogenous glucose production—thereby extending the functional impact of FBN3 beyond reproductive development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCorroborative case–control studies and meta-analyses have further reinforced an association between FBN3 markers (notably the D19S884 A8 allele) and an increased susceptibility to PCOS across diverse populations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Whole-exome sequencing in familial PCOS cases has also highlighted FBN3 as a candidate gene harboring rare, high-effect variants that may contribute to the complex etiology of the syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, emerging evidence extends the significance of FBN3 to craniofacial development; specific FBN3 single nucleotide polymorphisms have been linked with skeletal malocclusion, suggesting that FBN3 function is important not only for ovarian and metabolic homeostasis but also for the regulation of extracellular matrix architecture in craniofacial and connective tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Margrit Urbanek, Susan Sam, Richard S Legro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of a polycystic ovary syndrome susceptibility variant in fibrillin-3 and association with a metabolic phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2007-0761"}], "href": "https://doi.org/10.1210/jc.2007-0761"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17785364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17785364"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xing-Bing Cao, Yong Qiu, Xu-Sheng Qiu "}, {"type": "b", "children": [{"type": "t", "text": "[FBN3 gene polymorphisms in adolescent idiopathic scoliosis patients]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Yi Xue Za Zhi (2008)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19192405"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19192405"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mark J Prodoehl, Nicholas Hatzirodos, Helen F Irving-Rodgers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gap072"}], "href": "https://doi.org/10.1093/molehr/gap072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19692420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19692420"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nazia Raja-Khan, Allen R Kunselman, Laurence M Demers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A variant in the fibrillin-3 gene is associated with TGF-β and inhibin B levels in women with polycystic ovary syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Fertil Steril (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.fertnstert.2010.05.047"}], "href": "https://doi.org/10.1016/j.fertnstert.2010.05.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20630504"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20630504"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "C Diana Jordan, Sandra D Bohling, Noe L Charbonneau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fibrillins in adult human ovary and polycystic ovary syndrome: is fibrillin-3 affected in PCOS?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Histochem Cytochem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1369/jhc.2010.956615"}], "href": "https://doi.org/10.1369/jhc.2010.956615"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20855553"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20855553"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Laetitia Sabatier, Nicolai Miosge, Dirk Hubmacher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fibrillin-3 expression in human development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Matrix Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.matbio.2010.10.003"}], "href": "https://doi.org/10.1016/j.matbio.2010.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20970500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20970500"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Nicholas Hatzirodos, Rosemary A Bayne, Helen F Irving-Rodgers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Linkage of regulators of TGF-β activity in the fetal ovary to polycystic ovary syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.11-181099"}], "href": "https://doi.org/10.1096/fj.11-181099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21411746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21411746"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sudha K Yalamanchi, Susan Sam, Maria O Cardenas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of fibrillin-3 and transcription factor-7-like 2 gene variants with metabolic phenotypes in PCOS."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Obesity (Silver Spring) (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/oby.2011.400"}], "href": "https://doi.org/10.1038/oby.2011.400"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22301903"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22301903"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Guang-bin Xie, Pei Xu, Ye-na Che, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Microsatellite polymorphism in the fibrillin 3 gene and susceptibility to PCOS: a case-control study and meta-analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Biomed Online (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.rbmo.2012.10.014"}], "href": "https://doi.org/10.1016/j.rbmo.2012.10.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23265956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23265956"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Cengiz Karakaya, Aylin Pelin Çil, Kaya Bilguvar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Further delineation of familial polycystic ovary syndrome (PCOS) via whole-exome sequencing: PCOS-related rare FBN3 and FN1 gene variants are identified."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Obstet Gynaecol Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jog.15187"}], "href": "https://doi.org/10.1111/jog.15187"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35141985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35141985"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Adina Maria Topârcean, Arina Acatrinei, Ioana Rusu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic Insights into Skeletal Malocclusion: The Role of the FBN3 "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "rs7351083"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " SNP in the Romanian Population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicina (Kaunas) (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/medicina60071061"}], "href": "https://doi.org/10.3390/medicina60071061"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39064490"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39064490"}]}]}]}