title: Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries.
abstract: Several studies have demonstrated an association between polycystic ovary syndrome (PCOS) and the dinucleotide repeat microsatellite marker D19S884, which is located in intron 55 of the fibrillin-3 (FBN3) gene. Fibrillins, including FBN1 and 2, interact with latent transforming growth factor (TGF)-beta-binding proteins (LTBP) and thereby control the bioactivity of TGFbetas. TGFbetas stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, features feasibly influenced by abnormal fibrillin expression. To examine a possible role of fibrillins in PCOS, particularly FBN3, we undertook tagging and functional single nucleotide polymorphism (SNP) analysis (32 SNPs including 10 that generate non-synonymous amino acid changes) using DNA from 173 PCOS patients and 194 controls. No SNP showed a significant association with PCOS and alleles of most SNPs showed almost identical population frequencies between PCOS and control subjects. No significant differences were observed for microsatellite D19S884. In human PCO stroma/cortex (n = 4) and non-PCO ovarian stroma (n = 9), follicles (n = 3) and corpora lutea (n = 3) and in human ovarian cancer cell lines (KGN, SKOV-3, OVCAR-3, OVCAR-5), FBN1 mRNA levels were approximately 100 times greater than FBN2 and 200-1000-fold greater than FBN3. Expression of LTBP-1 mRNA was 3-fold greater than LTBP-2. We conclude that FBN3 appears to have little involvement in PCOS but cannot rule out that other markers in the region of chromosome 19p13.2 are associated with PCOS or that FBN3 expression occurs in other organs and that this may be influencing the PCOS phenotype.
authors.affiliation: Research Centre for Reproductive Health, Robinson Institute and School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Prodoehl
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hatzirodos
authors.forename: Helen F
authors.initials: HF
authors.lastname: Irving-Rodgers
authors.forename: Zhen Z
authors.initials: ZZ
authors.lastname: Zhao
authors.forename: Jodie N
authors.initials: JN
authors.lastname: Painter
authors.forename: Theresa E
authors.initials: TE
authors.lastname: Hickey
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gibson
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Carr
authors.forename: Helen D
authors.initials: HD
authors.lastname: Mason
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Norman
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Rodgers
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D005260:Female; D000071837:Fibrillins; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D010053:Ovary / Q000502:physiology*; D010641:Phenotype; D011085:Polycystic Ovary Syndrome / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C493782:FBN3 protein, human; D000071837:Fibrillins; D008840:Microfilament Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger
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