不明原因苗勒管发育异常患者LHX1基因的研究
摘要
背景女性生殖系统发育异常根据苗勒管发育程度不同,分为先天性无子宫无阴道(congenital absence of the uterus and vagina, CAUV),也称为Mayer-Rokitansky-Kuster-Hauser(MRKH)综合征、始基子宫、幼稚子宫、单角子宫、双角子宫、双子宫和子宫纵膈等不同表型,前三者几乎无生育能力,后四者从单纯的阴道纵隔到双子宫双宫颈等复杂畸形,都导致了较高的流产、早产或新生儿死亡发生,给患者带来了很大的身体和精神痛苦。然而,苗勒管发育异常的病因尚不清楚,国内对苗勒管发育异常的研究多数在手术治疗方面,对其病因的研究少见。为了更好地了解苗勒管发育异常的病因,我们收集了96位苗勒管发育异常患者资料,排除同时有性腺发育异常、先天性肾上腺皮质增生症、染色体异常及多系统畸形综合征等可明确诊断疾病,这些患者在母亲孕育状态、个人成长环境和所患疾病等方面未发现有明显特殊情况,且就目前研究观点,这种不明原因造成的生殖道畸形很可能与胚胎早期子宫内环境改变以及参与苗勒管发育的基因表达异常有关。子宫内环境的微小变化很难模拟,而根据现有的动物模型来推断参与苗勒管发育的基因并在患者中筛查较为可行,故本文对苗勒管发育异常分子遗传学研究进展进行了综述,并对苗勒管发育异常与LHX1基因编码区突变相关性进行了初步研究。LHX1基因位于17号染色体1区2带,编码包含2个LIM和1个HOX结构域的蛋白,LIM结构是唯一富含半胱氨酸的锌指蛋白结构的转录调控因子,参与细胞发育和分化的调控,而HOX结构域在发育中起关键调节作用已被公认。小鼠研究中表明LHX1基因对小鼠泌尿生殖系统中肾管、中肾、后肾和胎儿生殖腺育起关键性作用,在苗勒管上皮细胞中呈动态表达,与苗勒管在雌性中形成、分化和雄性中退化有关。Lhx1基因缺失的雌性小鼠有卵巢,但缺少子宫和输卵管。比较基因组杂交和全基因组分析都发现LHX1基因所在区域缺失与苗勒管发育异常相关联。国内尚无LHX1基因在苗勒管发育方面的研究。
目的探讨中国汉族不明原因苗勒管发育异常是否与LHX1基因突变相关。
方法选择96例中国汉族不明原因苗勒管发育异常患者(包括12例MRKH患者、11例始基子宫患者、7例幼稚子宫患者、25例单角合并或不合并残角子宫患者及41例子宫融合不全患者)和无明显苗勒管发育异常、月经规律且无自然流产史的正常对照105人,提取其外周血全基因组DNA,应用聚合酶链反应(PCR)扩增其5个外显子及相应侧翼序列,对PCR产物直接测序,与NCBI提供的正常序列比较,分析LHX1基因5个外显子是否存在异常碱基改变、插入或缺失。
结果与NCBI提供的正常序列比较,我们未在患者LHX1基因第1、2、3和4外显子区发现有意义的突变；在96例患者和147例对照人群LHX1基因第5外显子均发现一例存在一12bp的核苷酸片段杂合缺失c.2066-2077del,造成了4个氨基酸的丢失p.357-360delPro-Ser。患者的表现为单阴道双宫颈双子宫合并单肾畸形,曾行三次夫精人工授精(AIH)未孕；有此缺失的对照造影结果示子宫输卵管无明显畸形表现,因右侧输卵管妊娠保守治疗后未避孕未孕4年就诊,行2次体外受精-胚胎移植(IVF-ET)未孕。
结论及意义研究未发现中国汉族妇女未明原因的苗勒管发育异常与LHX1基因编码区序列改变相关,不明原因的苗勒管发育异常的发生原因还需进一步深入研究阐明。LHX1基因第5外显子c.2066-2077del改变为新发现的中国汉族人稀有多态位点(rare polymorphism),其与不孕症的相关性有待进一步研究。
BACKGROUNDS The female reproductive system anomalities include mullerian dysplasias and mullerian improper fusions, such as uterine agenesis, uincornuate uterus, uterus didelphys, bicornuate uterus and septate uterus. The formers are sterile and the latters with pure mediastinal vaginal or double uterus usually cause miscarriage, premature birth or neonate death. However, the genetics etiology of mullerian duct abnormalities (MA) is still unclear, to date only WNT4 mutions are detected in MA patients. LHX1, located in chromosome 17q12 and encodes a member of a large protein family with LIM domain, may function as a transcriptional regulator and be involved in control of differentiation and development of neural and lymphoid cells. Liml-null female mice had ovaries, but they lacked a uterus and oviduct. Recent researchs in MA patients by comparative genomics hybridization and the whole genome analysis found the imbalance or missing on 17q12 where LHX1 gene locates, which imply LHX1 may play important roles in Mullerian duct development.
OBJECTIVES To investigate whether or not LHX1 gene mutation existed in Han Chinese patients with Mullerian duct abnormalities of unknown cause.
METHODS LHX1 gene 5 exons was sequenced in a group of 96 Han Chinese patients (including 41 patients with incomplete Mullerian fusion,12 MRKH patients,11 primordial uterus,7 infantile uterus and 25 patients with unicornous uterus or rudimentary horn uterus) and 105 control individuals. The objective fragments were PCR-amplificated and sequenced, then compared with the normal sequences in NCBI.
RESULTS We have identified c.2066-2077del(p.357-360delPro-Ser) in the Exon5 of LHX1 gene in a double-uterus patient and a control sample.
CONCLUSIONS Mutation of LHX1 in coding regions may not be the correlated etiological factors involved in mullerian duct abnormalities in Han Chinese patients. We need more studies to elucidate the genetic etiology of Mullerian duct abnormalities in Chinese individuals. The deletion c.2066-2077del of LHX1 gene is a new rare polymorphism of Han Chinese. Further studies should focus on the relevance of infertility and the deletion.
目的探讨中国汉族不明原因苗勒管发育异常是否与LHX1基因突变相关。
方法选择96例中国汉族不明原因苗勒管发育异常患者(包括12例MRKH患者、11例始基子宫患者、7例幼稚子宫患者、25例单角合并或不合并残角子宫患者及41例子宫融合不全患者)和无明显苗勒管发育异常、月经规律且无自然流产史的正常对照105人,提取其外周血全基因组DNA,应用聚合酶链反应(PCR)扩增其5个外显子及相应侧翼序列,对PCR产物直接测序,与NCBI提供的正常序列比较,分析LHX1基因5个外显子是否存在异常碱基改变、插入或缺失。
结果与NCBI提供的正常序列比较,我们未在患者LHX1基因第1、2、3和4外显子区发现有意义的突变；在96例患者和147例对照人群LHX1基因第5外显子均发现一例存在一12bp的核苷酸片段杂合缺失c.2066-2077del,造成了4个氨基酸的丢失p.357-360delPro-Ser。患者的表现为单阴道双宫颈双子宫合并单肾畸形,曾行三次夫精人工授精(AIH)未孕；有此缺失的对照造影结果示子宫输卵管无明显畸形表现,因右侧输卵管妊娠保守治疗后未避孕未孕4年就诊,行2次体外受精-胚胎移植(IVF-ET)未孕。
结论及意义研究未发现中国汉族妇女未明原因的苗勒管发育异常与LHX1基因编码区序列改变相关,不明原因的苗勒管发育异常的发生原因还需进一步深入研究阐明。LHX1基因第5外显子c.2066-2077del改变为新发现的中国汉族人稀有多态位点(rare polymorphism),其与不孕症的相关性有待进一步研究。
BACKGROUNDS The female reproductive system anomalities include mullerian dysplasias and mullerian improper fusions, such as uterine agenesis, uincornuate uterus, uterus didelphys, bicornuate uterus and septate uterus. The formers are sterile and the latters with pure mediastinal vaginal or double uterus usually cause miscarriage, premature birth or neonate death. However, the genetics etiology of mullerian duct abnormalities (MA) is still unclear, to date only WNT4 mutions are detected in MA patients. LHX1, located in chromosome 17q12 and encodes a member of a large protein family with LIM domain, may function as a transcriptional regulator and be involved in control of differentiation and development of neural and lymphoid cells. Liml-null female mice had ovaries, but they lacked a uterus and oviduct. Recent researchs in MA patients by comparative genomics hybridization and the whole genome analysis found the imbalance or missing on 17q12 where LHX1 gene locates, which imply LHX1 may play important roles in Mullerian duct development.
OBJECTIVES To investigate whether or not LHX1 gene mutation existed in Han Chinese patients with Mullerian duct abnormalities of unknown cause.
METHODS LHX1 gene 5 exons was sequenced in a group of 96 Han Chinese patients (including 41 patients with incomplete Mullerian fusion,12 MRKH patients,11 primordial uterus,7 infantile uterus and 25 patients with unicornous uterus or rudimentary horn uterus) and 105 control individuals. The objective fragments were PCR-amplificated and sequenced, then compared with the normal sequences in NCBI.
RESULTS We have identified c.2066-2077del(p.357-360delPro-Ser) in the Exon5 of LHX1 gene in a double-uterus patient and a control sample.
CONCLUSIONS Mutation of LHX1 in coding regions may not be the correlated etiological factors involved in mullerian duct abnormalities in Han Chinese patients. We need more studies to elucidate the genetic etiology of Mullerian duct abnormalities in Chinese individuals. The deletion c.2066-2077del of LHX1 gene is a new rare polymorphism of Han Chinese. Further studies should focus on the relevance of infertility and the deletion.
引文
[1]Ribeiro SC, Tormena RA, Peterson TV,et al. Mullerian duct anomalies: review of current management. Sao Paulo Med J.2009,127(2):92-6.
[2]Pui MH. Imaging diagnosis of congenital uterine malformation. Comput Med Imaging Graph,2004,28:425-433.
[3]Cheroki C, Krepischi-Santos AC, Szuhai K, et al. Genomic imbalances associated with mullerian aplasia:Journal Of Medical Genetics. J Med Genet,2008, 45:228-232.
[4]Bernardini L, Gimelli S, Gervasini C, et al. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome:two case reports. Orphanet J Rare Dis,2009,4:25.
[5]Sasmira Lalwani, Hsin-hung Wu, Richard H, et al. HOXA10 mutations in congenital absence of uterus and vagina. Fertil Steril,2008,89:325-330.
[6]单英华,石玉华,许成岩等.58例苗勒管发育异常患者HOXA13基因分析.生殖与避孕,2007,27：178-181.
[7]A.Biason-Lauber, GDe Filippo, D.Konradl, et al. WNT4 deficiency-a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome:A Case Report. Hum Reprod,2007,22:224-229.
[8]Biason-Lauber A, Konrad D, Navratil F, et al. A WNT4 mutation associated with mullerian-duct regression and virilization in a 46,XX woman. New Eng. J. Med, 2004,351:792-798.
[9]Philibert P, Biason-Lauber A, Rouzier R, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities:a French collaborative study. J Clin Endocr Metab,2008,93:895-900.
[10]Mandel H, Shemer R, Borochowitz ZU, et al. SERKAL syndrome:an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am. J. Hum. Genet,2008,82:39-47.
[11]Timmreck LS, Pan HA, Reindollar RH, et al. WNT7A Mutations in Patients with Mullerian Duct Abnormalities, J Pediatr Adolesc Gynecol,2003,16:217-221.
[12]Carroll TJ, Park JS, Hayashi S, et al. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell,2005,9:283-292.
[13]Ravel C, Lorenco D, Dessolle L, et al. Mutational analysis of the WNT gene family in women with Mayer-Rokitansky-Kuster-Hauser syndrome. Fertil Steril,2009, 91:1604-1607.
[14]Erica Deutscher, Hung-Chang Yao H. Essential Roles of Mesenchyme-Derived Beta-Catenin in Mouse Mullerian duct Morphogenesis. Dev Biol,2007,307:227-236.
[15]Drummond JB, Rezende CF, Peixoto FC, et al. Molecular analysis of the P-catenin gene in patients with the Mayer-Rokitansky-Kuster-Hauser syndrome. J Assist Reprod Genet,2008,25:511-514.
[16]Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression of PAX2 in papillary serous carcinoma of the ovary:immunohistochemical evidence of fallopian tube or secondary Mullerian system origin?. Mod Pathol,2007,20:856-863.
[17]Timmreck LS, Gray MR, Handelin B, e tal. Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina. Am J Med Genet A,2003,120A(1):72-76.
[18]Davis RJ, Harding M, Moayedi Y, et al. Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis,2008,46:205-213
[19]Agnes Burel, Thomas Mouchel, Sylvie Odent, et al. Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). J Negat Results Biomed,2006,23:5-14.
[20]Cheroki C, Krepischi-Santos AC, Rosenberg C, et al. Report of a de122q11 in a patient with Mayer-Rokitansky-Kuster-Hauser (MRKH) anomaly and exclusion of WNT-4, RAR-gamma, and RXR-alpha as major genes determining MRKH anomaly in a study of 25 affected women. Am J Med Genet A,2006, 140(12):1339-1342.
[21]Tomaselli S, Megiorni F, De Barnardo C, e tal. Syndromic true hermaphroditism due to an R-spondinl (RSPO1) homozygous mutation. Hum Mutat, 2008,29:220-226.
[22]Sultan C, Biason-Lauber A, Philibert P. Mayer-Rokitansky-Kuster-Hauser syndrome:recent clinical and genetic findings. Gynecol Endocrinol,2009,25(l):8-11.
[23]Strissel PL, Oppelt P, Cupisti S, et al. Assessment of pituitary and steroid hormones and members of the TGF-beta superfamily for ovarian function in patients with congenital uterus and vaginal aplasia (MRKH syndrome). Horm Metab Res, 2009,41:408-413.
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[1]Ribeiro SC, Tormena RA, Peterson TV,et al. Mullerian duct anomalies: review of current management. Sao Paulo Med J.2009,127(2):92-6.
[2]Pui MH. Imaging diagnosis of congenital uterine malformation. Comput Med Imaging Graph,2004,28:425-433.
[3]Sasmira Lalwani, Hsin-hung Wu, Richard H, et al. HOXA10 mutations in congenital absence of uterus and vagina. Fertil Steril,2008,89:325-330.
[4]单英华,石玉华,许成岩等.58例苗勒管发育异常患者HOXA13基因分析.生殖与避孕,2007,27：178-181.
[5]A.Biason-Lauber, GDe Filippo, D.Konradl, et al. WNT4 deficiency-a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome:A Case Report. Hum Reprod,2007,22:224-229.
[6]Biason-Lauber A, Konrad D, Navratil F, et al. A WNT4 mutation associated with mullerian-duct regression and virilization in a 46,XX woman. New Eng. J. Med, 2004,351:792-798.
[7]Philibert P, Biason-Lauber A, Rouzier R, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities:a French collaborative study. J Clin Endocr Metab,2008,93:895-900.
[8]Mandel H, Shemer R, Borochowitz ZU, et al. SERKAL syndrome:an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am. J. Hum. Genet,2008,82:39-47.
[9]Timmreck LS, Pan HA, Reindollar RH, et al. WNT7A Mutations in Patients with Mullerian Duct Abnormalities, J Pediatr Adolesc Gynecol,2003,16:217-221.
[10]Carroll TJ, Park JS, Hayashi S, et al. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell,2005,9:283-292.
[11]Ravel C, Lorenco D, Dessolle L, et al. Mutational analysis of the WNT gene family in women with Mayer-Rokitansky-Kuster-Hauser syndrome. Fertil Steril,2009, 91:1604-1607.
[12]Cheroki C, Krepischi-Santos AC, Szuhai K, et al. Genomic imbalances associated with mullerian aplasia:Journal Of Medical Genetics. J Med Genet,2008, 45:228-232.
[13]Bernardini L, Gimelli S, Gervasini C, et al. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome:two case reports. Orphanet J Rare Dis,2009,4:25.
[14]Erica Deutscher, Hung-Chang Yao H. Essential Roles of Mesenchyme-Derived Beta-Catenin in Mouse Mullerian duct Morphogenesis. Dev Biol,2007,307:227-236.
[15]Drummond JB, Rezende CF, Peixoto FC, et al. Molecular analysis of the β-catenin gene in patients with the Mayer-Rokitansky-Kuster-Hauser syndrome. J Assist Reprod Genet,2008,25:511-514.
[16]Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression of PAX2 in papillary serous carcinoma of the ovary:immunohistochemical evidence of fallopian tube or secondary Mullerian system origin?. Mod Pathol,2007,20:856-863.
[17]Timmreck LS, Gray MR, Handelin B, e tal. Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina. Am J Med Genet A,2003,120A(1):72-76.
[18]Davis RJ, Harding M, Moayedi Y, et al. Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis,2008,46:205-213
[19]Agnes Burel, Thomas Mouchel, Sylvie Odent, et al. Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). J Negat Results Biomed,2006,23:5-14.
[20]Cheroki C, Krepischi-Santos AC, Rosenberg C, et al. Report of a del22q11 in a patient with Mayer-Rokitansky-Kuster-Hauser (MRKH) anomaly and exclusion of WNT-4, RAR-gamma, and RXR-alpha as major genes determining MRKH anomaly in a study of 25 affected women. Am J Med Genet A,2006, 140(12):1339-1342.
[21]Tomaselli S, Megiorni F, De Barnardo C, e tal. Syndromic true hermaphroditism due to an R-spondinl (RSPO1) homozygous mutation. Hum Mutat, 2008,29:220-226.
[22]Sultan C, Biason-Lauber A, Philibert P. Mayer-Rokitansky-Kuster-Hauser syndrome:recent clinical and genetic findings. Gynecol Endocrinol,2009,25(1):8-11.
[23]Strissel PL, Oppelt P, Cupisti S, et al. Assessment of pituitary and steroid hormones and members of the TGF-beta superfamily for ovarian function in patients with congenital uterus and vaginal aplasia (MRKH syndrome). Horm Metab Res, 2009,41:408-413.
[24]Lee HJ, Pazin DE, Kahlon RS, et al. Novel Markers of Early Ovarian Pre-granulosa Cells Are Expressedinan Sry-Like Pattern. Devl Dyn,2009, 238:812-825.
[2]Pui MH. Imaging diagnosis of congenital uterine malformation. Comput Med Imaging Graph,2004,28:425-433.
[3]Cheroki C, Krepischi-Santos AC, Szuhai K, et al. Genomic imbalances associated with mullerian aplasia:Journal Of Medical Genetics. J Med Genet,2008, 45:228-232.
[4]Bernardini L, Gimelli S, Gervasini C, et al. Recurrent microdeletion at 17q12 as a cause of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome:two case reports. Orphanet J Rare Dis,2009,4:25.
[5]Sasmira Lalwani, Hsin-hung Wu, Richard H, et al. HOXA10 mutations in congenital absence of uterus and vagina. Fertil Steril,2008,89:325-330.
[6]单英华,石玉华,许成岩等.58例苗勒管发育异常患者HOXA13基因分析.生殖与避孕,2007,27：178-181.
[7]A.Biason-Lauber, GDe Filippo, D.Konradl, et al. WNT4 deficiency-a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome:A Case Report. Hum Reprod,2007,22:224-229.
[8]Biason-Lauber A, Konrad D, Navratil F, et al. A WNT4 mutation associated with mullerian-duct regression and virilization in a 46,XX woman. New Eng. J. Med, 2004,351:792-798.
[9]Philibert P, Biason-Lauber A, Rouzier R, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities:a French collaborative study. J Clin Endocr Metab,2008,93:895-900.
[10]Mandel H, Shemer R, Borochowitz ZU, et al. SERKAL syndrome:an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am. J. Hum. Genet,2008,82:39-47.
[11]Timmreck LS, Pan HA, Reindollar RH, et al. WNT7A Mutations in Patients with Mullerian Duct Abnormalities, J Pediatr Adolesc Gynecol,2003,16:217-221.
[12]Carroll TJ, Park JS, Hayashi S, et al. Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell,2005,9:283-292.
[13]Ravel C, Lorenco D, Dessolle L, et al. Mutational analysis of the WNT gene family in women with Mayer-Rokitansky-Kuster-Hauser syndrome. Fertil Steril,2009, 91:1604-1607.
[14]Erica Deutscher, Hung-Chang Yao H. Essential Roles of Mesenchyme-Derived Beta-Catenin in Mouse Mullerian duct Morphogenesis. Dev Biol,2007,307:227-236.
[15]Drummond JB, Rezende CF, Peixoto FC, et al. Molecular analysis of the P-catenin gene in patients with the Mayer-Rokitansky-Kuster-Hauser syndrome. J Assist Reprod Genet,2008,25:511-514.
[16]Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression of PAX2 in papillary serous carcinoma of the ovary:immunohistochemical evidence of fallopian tube or secondary Mullerian system origin?. Mod Pathol,2007,20:856-863.
[17]Timmreck LS, Gray MR, Handelin B, e tal. Analysis of cystic fibrosis transmembrane conductance regulator gene mutations in patients with congenital absence of the uterus and vagina. Am J Med Genet A,2003,120A(1):72-76.
[18]Davis RJ, Harding M, Moayedi Y, et al. Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis,2008,46:205-213
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