title: Microsatellite in the 3' untranslated region of human fibroblast growth factor 9 (FGF9) gene exhibits pleiotropic effect on modulating FGF9 protein expression.
abstract: Fibroblast growth factor 9 (FGF9) is a member of secreted polypeptide families and involved in many important biological processes, including implantation and morphogenesis during embryogenesis and adult life. Recently, Fgf9-knockout mice exhibited male-to-female sex reversal, demonstrating a novel function for FGF9 in testicular development. We hypothesized that FGF9 is involved in sex development at an early embryonic stage in humans. In this study, we systematically screened sequences of the FGF9 gene in 21 XY females and 72 XX females and XY males to examine whether sequence variants of the FGF9 gene play a pathophysiological role on human gonadal dysgenesis. No mutation was identified, but a single nucleotide variant and two microsatellites were found. The allelic distribution of polymorphic microsatellite in the 3'-UTR of FGF9 between patients and controls was slightly different with Bonferroni correction (P=0.06). We further applied reporter gene system and quantitative RT-PCR to study the function of this microsatellite motif and results demonstrated that the (TG)(n) motif modulated gene expression at both pre- and post-transcriptional levels. The (TG)(14) allele, which showed a potential association with male-to-female sex reversal (odds ratio=6.08, 95% confidence interval=1.39-26.63), displayed the strongest promoter activity and longest mRNA stability. These data demonstrated that 3'-UTR microsatellite of the FGF9 is a functional polymorphism that plays dual roles in regulating FGF9 expression. Although our preliminary result suggested a possible association between FGF9 and human gonadal dysgenesis, the major limitation of small dataset in this study points out the requirement for further investigation.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Chen
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Hsu
authors.forename: Shaw-Jenq
authors.initials: SJ
authors.lastname: Tsai
authors.forename: Mong-Jen
authors.initials: MJ
authors.lastname: Chen
authors.forename: Chieh-Wei
authors.initials: CW
authors.lastname: Lin
authors.forename: H Sunny
authors.initials: HS
authors.lastname: Sun
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D012734:Disorders of Sex Development / Q000235:genetics; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D014644:Genetic Variation; D006609:High Mobility Group Proteins / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats / Q000502:physiology*; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; D006609:High Mobility Group Proteins; C490906:SOX1 protein, human; D055748:SOXB1 Transcription Factors; D008156:Luciferases