TY - JOUR
T1 - Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries
AU - Prodoehl, Mark J.
AU - Hatzirodos, Nicholas
AU - Irving-Rodgers, Helen F.
AU - Zhao, Zhen Z.
AU - Painter, Jodie N.
AU - Hickey, Theresa E.
AU - Gibson, Mark A.
AU - Rainey, William E.
AU - Carr, Bruce R.
AU - Mason, Helen D.
AU - Norman, Robert J.
AU - Montgomery, Grant W.
AU - Rodgers, Raymond J.
N1 - Funding Information:
We thank Professors Hajime Nawata and Toshihiko Yanase of Kyushu University and Professor Yoshihiro Nishi of Kurume University for the KGN cell line, Drs Suman Rice and Laura Pellatt for ovarian tissues, and Dr Carmela Ricciardelli and Miranda Ween for the cancer cell lines. Funding to pay the Open Access publication charges for this article was provided by the National Health and Medical Research Council of Australia.
Funding Information:
Funding to support this research was obtained from the National Health and Medical Research Council of Australia, University of Adelaide, the Clive and Vera Ramaciotti Foundation, the Wellcome Trust, and National Institute of Health, and Medical Research Council UK.
PY - 2009/8/19
Y1 - 2009/8/19
N2 - 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)-β-binding proteins (LTBP) and thereby control the bioactivity of TGFβs. TGFβs stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, fea-tures 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.
AB - 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)-β-binding proteins (LTBP) and thereby control the bioactivity of TGFβs. TGFβs stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, fea-tures 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.
KW - Fibrillin
KW - Latent-transforming growth factor β-binding protein
KW - Ovary
KW - Polycystic ovary syndrome
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U2 - 10.1093/molehr/gap072
DO - 10.1093/molehr/gap072
M3 - Article
C2 - 19692420
AN - SCOPUS:74049141946
SN - 1360-9947
VL - 15
SP - 829
EP - 841
JO - Molecular Human Reproduction
JF - Molecular Human Reproduction
IS - 12
M1 - gap072
ER -