Dixit Hridesh, Rao Lakshmi K, Padmalatha Venkata V, Kanakavalli Murthy, Deenadayal Mamata, Gupta Nalini, Chakrabarty Baidyanath, Singh Lalji
Centre for Cellular and Molecular Biology, Uppal Road, 500007, Hyderabad, AP, India.
Hum Genet. 2006 May;119(4):408-15. doi: 10.1007/s00439-006-0150-0. Epub 2006 Mar 1.
Premature ovarian failure (POF) is an unexplained amenorrhoea (>6 months) with raised levels of gonadotropins (FSH>40 U/L) occurring before the age of 40 years. Recent studies have elucidated the role of oocyte derived growth factors (BMP15 and GDF9) in maintenance of folliculogenesis, granulosa cell (GC) proliferation and overall fertility. Our recently published work showed presence of two rare missense variants in the GDF9 gene associated with ovarian failure (Dixit et al. 2005, Menopause 12:749-754). The present case-control study has been structured to establish the role of BMP15 germline status associated with ovarian failure. Sequence analysis of the coding region of the BMP15 gene was carried out in a cohort of women with POF (n=133), primary amenorrhoea (n=60), and secondary amenorrhoea (n=9) compared with control females (n=197). This study revealed a total of 18 germline variants in the coding region of BMP15 gene, including 16 novel variants. These novel variants include one intronic variant, one 3' flanking variant, one silent variant, and 13 missense variants. Eleven missense variants were present only in cases with complete absence in the control females. The remaining two missense variants viz. c.308A>G (p.Asn103Ser) and c.788_789insTCT (p.Leu263_Arg264insLeu) were present both in the cases and in the controls. The c.788_789insTCT variant was significantly higher in primary amenorrhoea cases than in the controls (Fisher's exact test, P=0.034). Three frequent variants c.-9C>G, c.308A>G, and c.852C>T were chosen for haplotyping. The haplotype G-G-C was found to be significantly associated with ovarian failure (P=0.0075). In a nutshell, the BMP15 gene is highly associated with etiology of ovarian failure.
卵巢早衰（POF）是指在40岁之前出现不明原因的闭经（>6个月）且促性腺激素水平升高（促卵泡生成素>40 U/L）。最近的研究阐明了卵母细胞衍生生长因子（骨形态发生蛋白15，即BMP15和生长分化因子9，即GDF9）在维持卵泡发生、颗粒细胞（GC）增殖和整体生育能力中的作用。我们最近发表的研究表明，GDF9基因中存在两个与卵巢早衰相关的罕见错义变体（迪克西特等人，2005年，《更年期》12:749 - 754）。本病例对照研究旨在确定与卵巢早衰相关的BMP15种系状态的作用。对一组卵巢早衰女性（n = 133）、原发性闭经女性（n = 60）和继发性闭经女性（n = 9）的BMP15基因编码区进行序列分析，并与对照女性（n = 197）进行比较。该研究在BMP15基因编码区共发现18种种系变体，其中包括16种新变体。这些新变体包括1种内含子变体、1种3'侧翼变体、1种沉默变体和13种错义变体。11种错义变体仅存在于病例中，对照女性中完全没有。其余两种错义变体，即c.308A>G（p.Asn103Ser）和c.788_789insTCT（p.Leu263_Arg264insLeu）在病例和对照中均有出现。c.788_789insTCT变体在原发性闭经病例中的出现频率显著高于对照（Fisher精确检验，P = 0.034）。选择了三个常见变体c.-9C>G、c.308A>G和c.852C>T进行单倍型分析。发现单倍型G - G - C与卵巢早衰显著相关（P = 0.0075）。简而言之，BMP15基因与卵巢早衰的病因高度相关。
