尿道下裂的基因特点及其研究进展
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摘要
尿道下裂是男性新生儿中常见的先天性泌尿系统畸形。主要是由阴茎和尿道发育异常引起的,是一种多因素疾病,个体差异明显。目前研究发现,多种因素均与尿道下裂有关,包括遗传因素、产前激素不足、母体胎盘因素及环境影响,因此,尿道下裂往往是多因素结合的产物。在过去的十年间,大量研究致力于揭示尿道下裂的遗传基因特点。这些研究包括骨形成蛋白(BMP)、成纤维细胞生长因子(FGF)、同源盒基因A(HOXA)等基因,涵盖了性别基因的转录、性激素的合成及相关基因的信号传导。尽管目前发现了大量尿道下裂相关基因,但仍需大样本病例临床对照研究明确这些基因的诊断效能及生物学意义。同时,随着测序技术的发展,外显子和全基因组测序也将揭示基因与基因、基因与环境的相互作用,更好地探索尿道下裂的分子机制,从而探寻合适分子标记物及治疗干预的靶点。综述这一领域的研究现状,并对一些与尿道下裂有关基因的研究进展进行探讨。
Hypospadias, one of the most common congenital malformations in male neonates, is due to abnormal penis and urethral development. It is a highly heterogeneous disorder that is related to multiple factors including genetic factor, hormonal insufficient, maternal and placental factor and environment factor. During the last decade, a tremendous work has been devoted to the molecular genetics of isolated hypospadias including the study of BMP, FGF, HOXA and so on. The related genes covered gender, steroidogenesis and signaling genes. It is necessary to study the biological functions of those genes and potential application in diagnosis by the case-control study with large samples. With the development of sequencing technique, the interaction of gene-gene or geneenvironment will be decoded through new exome sequencing and whole genome sequencing, which is helpful for us to understand better the molecular mechanism of hypospadias and to explore the diagnosis markers and therapy targets. In this paper, we review the genetic factors of hypospadias and the research progress.
Hypospadias, one of the most common congenital malformations in male neonates, is due to abnormal penis and urethral development. It is a highly heterogeneous disorder that is related to multiple factors including genetic factor, hormonal insufficient, maternal and placental factor and environment factor. During the last decade, a tremendous work has been devoted to the molecular genetics of isolated hypospadias including the study of BMP, FGF, HOXA and so on. The related genes covered gender, steroidogenesis and signaling genes. It is necessary to study the biological functions of those genes and potential application in diagnosis by the case-control study with large samples. With the development of sequencing technique, the interaction of gene-gene or geneenvironment will be decoded through new exome sequencing and whole genome sequencing, which is helpful for us to understand better the molecular mechanism of hypospadias and to explore the diagnosis markers and therapy targets. In this paper, we review the genetic factors of hypospadias and the research progress.
引文
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[15]李恩惠,魏海彬,黄邦高,等.邻苯二甲酸二丁酯导致雄性大鼠子鼠尿道下裂畸形及其机制研究[J].中华男科学杂志,2017,23(12):1063-1068.
[16]Cao L,Chen C,Leng Y,et al.A missense mutation of HOXA13underlies hand-foot-genital syndrome in a Chinese family[J].JGenet,2017,96(4):647-652.
[17]Nelson P,Nieuwenhuijsen M,Jensen TK,et al.Prevalence of hypospadias in the same geographic region as ascertained by three different registries[J].Birth Defects Res A Clin Mol Teratol,2007,79(10):685-687.
[18]Leung MC,Hutson MS,Seifert AW,et al.Computational modeling and simulation of genital tubercle development[J].Reprod Toxicol,2016,64:151-161.
[19]Chen Y,Yu H,Pask AJ,et al.Hormone-responsive genes in the SHH and WNT/β-catenin signaling pathways influence urethral closure and phallus growth[J].Biol Reprod,2018,99(4):806-816.
[20]Sun L,Zhou M,Liu T.Association between SRD5A2 polymorphism and hypospadias:a meta-analysis[J].Pharmazie,2019,74(2):125-128.
[21]Sharma S,Sandhowe-Klaverkamp R,Schlatt S.Differentiation of Testis Xenografts in the Prepubertal Marmoset Depends on the Sex and Status of the Mouse Host[J].Front Endocrinol(Lausanne),2018,9:467.
[22]Ratan SK,Aggarwal SK,Mishra TK,et al.Hormonal profile in children with isolated hypospadias associates better with comprehensive score of local anatomical factors as compared to meatal location or degree of chordee[J].Indian J Endocrinol Metab,2014,18(4):558-564.
[23]Zhu YP,Li EH,Sun WL,et al.Maternal exposure to di-n-butyl phthalate(DBP)induces combined anorectal and urogenital malformations in male rat offspring[J].Reprod Toxicol,2016,61:169-176.
[24]Moriya K,Nakamura M,Kon M,et al.Risk factors affecting postpubertal high serum follicle-stimulating hormone in patients with hypospadias[J].World J Urol,2019,[Epub ahead of print].
[25]Liu S,Wang Z,Jiang J,et al.Severe forms of complete androgen insensitivity syndrome caused by a p.Q65X novel mutation in androgen receptor:Clinical manifestations,imaging findings and molecular genetics[J].Steroids,2019,144:47-51.
[26]Nordenvall AS,Paucar M,Almqvist C,et al.Hypospadias as a novel feature in spinal bulbar muscle atrophy[J].J Neurol,2016,263(4):703-706.
[27]Hornig NC,Ukat M,Schweikert HU,et al.Identification of an ARMutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity[J].J Clin Endocrinol Metab,2016,101(11):4468-4477.
[28]Hozyasz KK,Mostowska A,Kowal A,et al.Further Evidence of the Association of the Diacylglycerol Kinase Kappa(DGKK)Gene With Hypospadias[J].Urol J,2018,15(5):272-276.
[29]Carmichael SL,Yang W,Ma C,et al.Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk[J].Birth Defects Res A Clin Mol Teratol,2016,106(8):653-658.
[30]Liu Y,Ye W,Wu M,et al.Association of MAMLD1 singlenucleotide polymorphisms with hypospadias in Chinese Han population[J].Front Biosci(Landmark Ed),2017,22:1173-1176.
[31]Zhao J,Li X,Guo M,et al.The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300and H3K27ac for transcriptional regulation[J].BMC Genomics,2016,17:335.
[32]Kalfa N,Liu B,Klein O,et al.Genomic variants of ATF3 in patients with hypospadias[J].J Urol,2008,180(5):2183-2188.
[2]Bouty A,Ayers KL,Pask A,et al.The Genetic and Environmental Factors Underlying Hypospadias[J].Sex Dev,2015,9(5):239-259.
[3]Acar S,Tuhan H,Bora E,et al.Identification of an AR mutation in Klinefelter syndrome during evaluation for penoscrotal hypospadias[J].Hormones(Athens),2017,16(3):313-317.
[4]Donaire AE,Mendez MD.Hypospadias[EB/OL].[2019-02-23].https://www.ncbi.nlm.nih.gov/books/NBK482122/.
[5]Brouwers MM,van der Zanden LF,de Gier RP,et al.Hypospadias:risk factor patterns and different phenotypes[J].BJU Int,2010,105(2):254-262.
[6]van der Zanden LF,van Rooij IA,Feitz WF,et al.Aetiology of hypospadias:a systematic review of genes and environment[J].Hum Reprod Update,2012,18(3):260-283.
[7]Joodi M,Amerizadeh F,Hassanian SM,et al.The genetic factors contributing to hypospadias and their clinical utility in its diagnosis[J].J Cell Physiol,2019,234(5):5519-5523.
[8]Diposarosa R,Pamungkas KO,Sribudiani Y,et al.Description of mutation spectrum and polymorphism of Wilms'tumor 1(WT1)gene in hypospadias patients in the Indonesian population[J].JPediatr Urol,2018,14(3):237.e1-237.e7.
[9]Colson C,Aubry E,Cartigny M,et al.SF1 and spleen development:new heterozygous mutation,literature review and consequences for NR5A1-mutated patient's management[J].Clin Genet,2017,92(1):99-103.
[10]Sreenivasan R,Gordon CT,Benko S,et al.Altered SOX9 genital tubercle enhancer region in hypospadias[J].J Steroid Biochem Mol Biol,2017,170:28-38.
[11]Miyado M,Muroya K,Katsumi M,et al.Somatically Acquired Isodicentric Y and Mosaic Loss of Chromosome Y in a Boy with Hypospadias[J].Cytogenet Genome Res,2018,154(3):122-125.
[12]Nikolaev VV,Solontsov YN.Epidemiology and theories of the origin of hypospadias[J].Urologiia,2018,(3):141-145.
[13]Tas E,Sebastian J,Madan-Khetarpal S,et al.Familial deletion of the HOXA gene cluster associated with Hand-Foot-Genital syndrome and phenotypic variability[J].Am J Med Genet A,2017,173(1):221-224.
[14]Yakushiji-Kaminatsui N,Lopez-Delisle L,Bolt CC,et al.Similarities and differences in the regulation of HoxD genes during chick and mouse limb development[J].PLoS Biol,2018,16(11):e3000004.
[15]李恩惠,魏海彬,黄邦高,等.邻苯二甲酸二丁酯导致雄性大鼠子鼠尿道下裂畸形及其机制研究[J].中华男科学杂志,2017,23(12):1063-1068.
[16]Cao L,Chen C,Leng Y,et al.A missense mutation of HOXA13underlies hand-foot-genital syndrome in a Chinese family[J].JGenet,2017,96(4):647-652.
[17]Nelson P,Nieuwenhuijsen M,Jensen TK,et al.Prevalence of hypospadias in the same geographic region as ascertained by three different registries[J].Birth Defects Res A Clin Mol Teratol,2007,79(10):685-687.
[18]Leung MC,Hutson MS,Seifert AW,et al.Computational modeling and simulation of genital tubercle development[J].Reprod Toxicol,2016,64:151-161.
[19]Chen Y,Yu H,Pask AJ,et al.Hormone-responsive genes in the SHH and WNT/β-catenin signaling pathways influence urethral closure and phallus growth[J].Biol Reprod,2018,99(4):806-816.
[20]Sun L,Zhou M,Liu T.Association between SRD5A2 polymorphism and hypospadias:a meta-analysis[J].Pharmazie,2019,74(2):125-128.
[21]Sharma S,Sandhowe-Klaverkamp R,Schlatt S.Differentiation of Testis Xenografts in the Prepubertal Marmoset Depends on the Sex and Status of the Mouse Host[J].Front Endocrinol(Lausanne),2018,9:467.
[22]Ratan SK,Aggarwal SK,Mishra TK,et al.Hormonal profile in children with isolated hypospadias associates better with comprehensive score of local anatomical factors as compared to meatal location or degree of chordee[J].Indian J Endocrinol Metab,2014,18(4):558-564.
[23]Zhu YP,Li EH,Sun WL,et al.Maternal exposure to di-n-butyl phthalate(DBP)induces combined anorectal and urogenital malformations in male rat offspring[J].Reprod Toxicol,2016,61:169-176.
[24]Moriya K,Nakamura M,Kon M,et al.Risk factors affecting postpubertal high serum follicle-stimulating hormone in patients with hypospadias[J].World J Urol,2019,[Epub ahead of print].
[25]Liu S,Wang Z,Jiang J,et al.Severe forms of complete androgen insensitivity syndrome caused by a p.Q65X novel mutation in androgen receptor:Clinical manifestations,imaging findings and molecular genetics[J].Steroids,2019,144:47-51.
[26]Nordenvall AS,Paucar M,Almqvist C,et al.Hypospadias as a novel feature in spinal bulbar muscle atrophy[J].J Neurol,2016,263(4):703-706.
[27]Hornig NC,Ukat M,Schweikert HU,et al.Identification of an ARMutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity[J].J Clin Endocrinol Metab,2016,101(11):4468-4477.
[28]Hozyasz KK,Mostowska A,Kowal A,et al.Further Evidence of the Association of the Diacylglycerol Kinase Kappa(DGKK)Gene With Hypospadias[J].Urol J,2018,15(5):272-276.
[29]Carmichael SL,Yang W,Ma C,et al.Joint effects of genetic variants and residential proximity to pesticide applications on hypospadias risk[J].Birth Defects Res A Clin Mol Teratol,2016,106(8):653-658.
[30]Liu Y,Ye W,Wu M,et al.Association of MAMLD1 singlenucleotide polymorphisms with hypospadias in Chinese Han population[J].Front Biosci(Landmark Ed),2017,22:1173-1176.
[31]Zhao J,Li X,Guo M,et al.The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300and H3K27ac for transcriptional regulation[J].BMC Genomics,2016,17:335.
[32]Kalfa N,Liu B,Klein O,et al.Genomic variants of ATF3 in patients with hypospadias[J].J Urol,2008,180(5):2183-2188.