Pierre-Robin综合征的遗传调控机制
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摘要
Pierre-Robin综合征(Pierre-Robin syndrome,PRS)是一种能引起颅面器官异常的遗传性疾病,主要表现为下颌发育不全、舌后坠和腭裂等,可导致新生儿喂食困难,甚至危及个体生命的阻塞性呼吸暂停,是先天性颅面畸形中较为常见的一种综合征。该综合征在全球的发病率为1/8 500~1/14 000,不仅影响个体的生长发育还影响其受教育程度,受到社会的广泛关注。虽然Pierre-Robin综合征的临床特征明显,易于诊断,但不同患者间高相似性的表型很容易掩盖患病个体之间的病理学异质性,从而很难确定每例Pierre-Robin综合征的具体病因。因此,了解Pierre-Robin综合征的发病原理及其遗传机制,对于防治Pierre-Robin综合征尤为重要。基于此,本文结合新近几年在Pierre-Robin综合征发病机制方面的相关研究,主要对引起该综合征的关键信号通路及其相关分子机制,特别是不同信号通路间的相互作用机制进行综述,从而进一步理解Pierre-Robin综合征发生的遗传调控机制。
Pierre-Robin syndrome is a congenital craniofacial malformation containing mandibular hypoplasia,glossoptosis, and cleft palate leading to feeding difficulties and even life-threatening obstructive apnea in newborn infants. It occurs in 1/8 500 to 1/14 000 births. The malformation affects not only growth but also long-term education of patients. Though the diagnosis of Pierre-Robin syndrome is readily recognizable by clinical features,the phenotypic similarity conceals etiological heterogeneity among individuals,making it difficult to find out the specific genetic cause in each individual of PierreRobin syndrome. Therefore, to reveal the genetic mechanism of Pierre-Robin syndrome becomes particularly important. In this review,we introduce the latest studies on the pathogenesis and molecular mechanism of Pierre-Robin syndrome. Our review provides important references for further understanding of genetic control of Pierre-Robin syndrome.
Pierre-Robin syndrome is a congenital craniofacial malformation containing mandibular hypoplasia,glossoptosis, and cleft palate leading to feeding difficulties and even life-threatening obstructive apnea in newborn infants. It occurs in 1/8 500 to 1/14 000 births. The malformation affects not only growth but also long-term education of patients. Though the diagnosis of Pierre-Robin syndrome is readily recognizable by clinical features,the phenotypic similarity conceals etiological heterogeneity among individuals,making it difficult to find out the specific genetic cause in each individual of PierreRobin syndrome. Therefore, to reveal the genetic mechanism of Pierre-Robin syndrome becomes particularly important. In this review,we introduce the latest studies on the pathogenesis and molecular mechanism of Pierre-Robin syndrome. Our review provides important references for further understanding of genetic control of Pierre-Robin syndrome.
引文
[1]Gangopadhyay N,Mendonca DA,Woo AS.Pierre robin sequence[J].Semin Plast Surg,2012,26(2):76-82
[2]Izumi K,Konczal LL,Mitchell AL,et al.Underlying genetic diagnosis of Pierre Robin sequence:retrospective chart review at two children’s hospitals and a systematic literature review[J].J Pediatr,2012,160(4):645-650.e2
[3]Brewer FR,Harper LM.Pierre Robin Sequence[M].Obstetric Imaging:Fetal Diagnosis and Care(Second Edition).Elsevier,2018:570-572
[4]Hunt JA,Hobar PC.Common craniofacial anomalies:the facial dysostoses[J].Plast Reconstr Surg,2002,110(7):1714-1725
[5]Paes EC,de Vries IAC,Penris WM,et al.Growth and prevalence of feeding difficulties in children with Robin sequence:a retrospective cohort study[J].Clin Oral Investig,2017,21(6):2063-2076
[6]Fronczak P,Skarzynski P,Dziendziel B,et al.Problems in treatment of tinnitus and hearing loss in a Pierre Robin syndrome[J].J Hear Sci,2017,7(2)
[7]Tan TY,Kilpatrick N,Farlie PG.Developmental and genetic perspectives on Pierre Robin sequence[J].Am J Med Genet C Semin Med Genet,2013,163C(4):295-305
[8]Pasetti M,Mazzoleni F,Novelli G,et al.Temporomandibular joint ankylosis as part of the clinical spectrum of Carey-FinemanZiter syndrome?[J].Am J Med Genet A,2016,170(8):2191-2195
[9]Basart H,Paes EC,Maas SM,et al.Etiology and pathogenesis of robin sequence in a large Dutch cohort[J].Am J Med Genet A,2015,167A(9):1983-1992
[10]Evans AK,Rahbar R,Rogers GF,et al.Robin sequence:a retrospective review of 115 patients[J].Int J Pediatr Otorhinolaryngol,2006,70(6):973-980
[11]Dudas M,Sridurongrit S,Nagy A,et al.Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells[J].Mech Dev,2004,121(2):173-182
[12]Li L,Lin M,Wang Y,et al.Bmprla is required in mesenchymal tissue and has limited redundant function with Bmprlb in tooth and palate development[J].Dev Biol,2011,349(2):451-461
[13]Li L,Wang Y,Lin M,et al.Augmented BMPRIA-mediated BMP signaling in cranial neural crest lineage leads to cleft palate formation and delayed tooth differentiation[J].PLo S One,2013,8(6):e66107
[14]Yang Y,Yuan J,Yao X,et al.BMPR1B mutation causes Pierre Robin sequence[J].Oncotarget,2017,8(16):25864-25871
[15]Song Z,Liu C,Iwata J,et al.Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development[J].J Biol Chem,2013,288(15):10440-10450
[16]Murakami S,Kan M,Mc Keehan WL,et al.Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway[J].Proc Natl Acad Sci U S A,2000,97(3):1113-1118
[17]Bobick BE,Kulyk WM.The MEK-ERK signaling pathway is a negative regulator of cartilage-specific gene expression in embryonic limb mesenchyme[J].J Biol Chem,2004,279(6):4588-4595
[18]Bobick BE,Kulyk WM.MEK-ERK signaling plays diverse roles in the regulation of facial chondrogenesis[J].Exp Cell Res,2006,312(7):1079-1092
[19]Newbern J,Zhong J,Wickramasinghe RS,et al.Mouse and human phenotypes indicate a critical conserved role for ERK2signaling in neural crest development[J].Proc Natl Acad Sci U S A,2008,105(44):17115-17120
[20]Parada C,Han D,Grimaldi A,et al.Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence[J].Development,2015,142(21):3734-3745
[21]Chew LJ,Gallo V.The Yin and Yang of Sox proteins:Activation and repression in development and disease[J].J Neurosci Res,2009,87(15):3277-3287
[22]Bowles J,Schepers G,Koopman P.Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators[J].Dev Biol,2000,227(2):239-255
[23]Mori-Akiyama Y,Akiyama H,Rowitch DH,et al.Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest[J].Proc Natl Acad Sci U S A,2003,100(16):9360-9365
[24]Ng LJ,Wheatley S,Muscat GE,et al.SOX9 binds DNA,activates transcription,and coexpresses with type II collagen during chondrogenesis in the mouse[J].Dev Biol,1997,183(1):108-121
[25]Zhao Q,Eberspaecher H,Lefebvre V,et al.Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis[J].Dev Dyn,1997,209(4):377-386
[26]Akiyama H,Chaboissier MC,Martin JF,et al.The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6[J].Genes Dev,2002,16(21):2813-2828
[27]Foster JW,Dominguez-Steglich MA,Guioli S,et al.Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene[J].Nature,1994,372(6506):525-530
[28]Wagner T,Wirth J,Meyer J,et al.Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9[J].Cell,1994,79(6):1111-1120
[29]Benko S,Fantes JA,Amiel J,et al.Highly conserved noncoding elements on either side of SOX9 associated with Pierre Robin sequence[J].Nat Genet,2009,41(3):359-364
[30]Gordon CT,Attanasio C,Bhatia S,et al.Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence[J].Hum Mutat,2014,35(8):1011-1020
[31]Bi W,Huang W,Whitworth DJ,et al.Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization[J].Proc Natl Acad Sci U S A,2001,98(12):6698-6703
[32]Sock E,Rettig SD,Enderich J,et al.Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling[J].Mol Cell Biol,2004,24(15):6635-6644
[33]Huang H,Yang X,Bao M,et al.Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence[J].J Biol Chem,2016,291(13):7107-7118
[34]Lei R,Zhang K,Liu K,et al.Transferrin receptor facilitates TGF-βand BMP signaling activation to control craniofacial morphogenesis[J].Cell Death Dis,2016,7(6):e2282
[35]Oka K,Oka S,Hosokawa R,et al.TGF-beta mediated Dlx5signaling plays a crucial role in osteo-chondroprogenitor cell lineage determination during mandible development[J].Dev Biol,2008,321(2):303-309
[36]Furumatsu T,Tsuda M,Taniguchi N,et al.Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment[J].J Biol Chem,2005,280(9):8343-8350
[37]Semba I,Nonaka K,Takahashi I,et al.Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2[J].Dev Dyn,2000,217(4):401-414
[38]Pan Q,Yu Y,Chen Q,et al.Sox9,a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis,is activated through BMP pathway and a CCAAT box in the proximal promoter[J].J Cell Physiol,2008,217(1):228-241
[39]Bobick BE,Thornhill TM,Kulyk WM.Fibroblast growth factors2,4,and 8 exert both negative and positive effects on limb,frontonasal,and mandibular chondrogenesis via MEK-ERK activation[J].J Cell Physiol,2007,211(1):233-243
[40]Terao F,Takahashi I,Mitani H,et al.Fibroblast growth factor10 regulates Meckel’s cartilage formation during early mandibular morphogenesis in rats[J].Dev Biol,2011,350(2):337-347
[2]Izumi K,Konczal LL,Mitchell AL,et al.Underlying genetic diagnosis of Pierre Robin sequence:retrospective chart review at two children’s hospitals and a systematic literature review[J].J Pediatr,2012,160(4):645-650.e2
[3]Brewer FR,Harper LM.Pierre Robin Sequence[M].Obstetric Imaging:Fetal Diagnosis and Care(Second Edition).Elsevier,2018:570-572
[4]Hunt JA,Hobar PC.Common craniofacial anomalies:the facial dysostoses[J].Plast Reconstr Surg,2002,110(7):1714-1725
[5]Paes EC,de Vries IAC,Penris WM,et al.Growth and prevalence of feeding difficulties in children with Robin sequence:a retrospective cohort study[J].Clin Oral Investig,2017,21(6):2063-2076
[6]Fronczak P,Skarzynski P,Dziendziel B,et al.Problems in treatment of tinnitus and hearing loss in a Pierre Robin syndrome[J].J Hear Sci,2017,7(2)
[7]Tan TY,Kilpatrick N,Farlie PG.Developmental and genetic perspectives on Pierre Robin sequence[J].Am J Med Genet C Semin Med Genet,2013,163C(4):295-305
[8]Pasetti M,Mazzoleni F,Novelli G,et al.Temporomandibular joint ankylosis as part of the clinical spectrum of Carey-FinemanZiter syndrome?[J].Am J Med Genet A,2016,170(8):2191-2195
[9]Basart H,Paes EC,Maas SM,et al.Etiology and pathogenesis of robin sequence in a large Dutch cohort[J].Am J Med Genet A,2015,167A(9):1983-1992
[10]Evans AK,Rahbar R,Rogers GF,et al.Robin sequence:a retrospective review of 115 patients[J].Int J Pediatr Otorhinolaryngol,2006,70(6):973-980
[11]Dudas M,Sridurongrit S,Nagy A,et al.Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells[J].Mech Dev,2004,121(2):173-182
[12]Li L,Lin M,Wang Y,et al.Bmprla is required in mesenchymal tissue and has limited redundant function with Bmprlb in tooth and palate development[J].Dev Biol,2011,349(2):451-461
[13]Li L,Wang Y,Lin M,et al.Augmented BMPRIA-mediated BMP signaling in cranial neural crest lineage leads to cleft palate formation and delayed tooth differentiation[J].PLo S One,2013,8(6):e66107
[14]Yang Y,Yuan J,Yao X,et al.BMPR1B mutation causes Pierre Robin sequence[J].Oncotarget,2017,8(16):25864-25871
[15]Song Z,Liu C,Iwata J,et al.Mice with Tak1 deficiency in neural crest lineage exhibit cleft palate associated with abnormal tongue development[J].J Biol Chem,2013,288(15):10440-10450
[16]Murakami S,Kan M,Mc Keehan WL,et al.Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway[J].Proc Natl Acad Sci U S A,2000,97(3):1113-1118
[17]Bobick BE,Kulyk WM.The MEK-ERK signaling pathway is a negative regulator of cartilage-specific gene expression in embryonic limb mesenchyme[J].J Biol Chem,2004,279(6):4588-4595
[18]Bobick BE,Kulyk WM.MEK-ERK signaling plays diverse roles in the regulation of facial chondrogenesis[J].Exp Cell Res,2006,312(7):1079-1092
[19]Newbern J,Zhong J,Wickramasinghe RS,et al.Mouse and human phenotypes indicate a critical conserved role for ERK2signaling in neural crest development[J].Proc Natl Acad Sci U S A,2008,105(44):17115-17120
[20]Parada C,Han D,Grimaldi A,et al.Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence[J].Development,2015,142(21):3734-3745
[21]Chew LJ,Gallo V.The Yin and Yang of Sox proteins:Activation and repression in development and disease[J].J Neurosci Res,2009,87(15):3277-3287
[22]Bowles J,Schepers G,Koopman P.Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators[J].Dev Biol,2000,227(2):239-255
[23]Mori-Akiyama Y,Akiyama H,Rowitch DH,et al.Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest[J].Proc Natl Acad Sci U S A,2003,100(16):9360-9365
[24]Ng LJ,Wheatley S,Muscat GE,et al.SOX9 binds DNA,activates transcription,and coexpresses with type II collagen during chondrogenesis in the mouse[J].Dev Biol,1997,183(1):108-121
[25]Zhao Q,Eberspaecher H,Lefebvre V,et al.Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis[J].Dev Dyn,1997,209(4):377-386
[26]Akiyama H,Chaboissier MC,Martin JF,et al.The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6[J].Genes Dev,2002,16(21):2813-2828
[27]Foster JW,Dominguez-Steglich MA,Guioli S,et al.Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene[J].Nature,1994,372(6506):525-530
[28]Wagner T,Wirth J,Meyer J,et al.Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9[J].Cell,1994,79(6):1111-1120
[29]Benko S,Fantes JA,Amiel J,et al.Highly conserved noncoding elements on either side of SOX9 associated with Pierre Robin sequence[J].Nat Genet,2009,41(3):359-364
[30]Gordon CT,Attanasio C,Bhatia S,et al.Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence[J].Hum Mutat,2014,35(8):1011-1020
[31]Bi W,Huang W,Whitworth DJ,et al.Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization[J].Proc Natl Acad Sci U S A,2001,98(12):6698-6703
[32]Sock E,Rettig SD,Enderich J,et al.Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling[J].Mol Cell Biol,2004,24(15):6635-6644
[33]Huang H,Yang X,Bao M,et al.Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence[J].J Biol Chem,2016,291(13):7107-7118
[34]Lei R,Zhang K,Liu K,et al.Transferrin receptor facilitates TGF-βand BMP signaling activation to control craniofacial morphogenesis[J].Cell Death Dis,2016,7(6):e2282
[35]Oka K,Oka S,Hosokawa R,et al.TGF-beta mediated Dlx5signaling plays a crucial role in osteo-chondroprogenitor cell lineage determination during mandible development[J].Dev Biol,2008,321(2):303-309
[36]Furumatsu T,Tsuda M,Taniguchi N,et al.Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment[J].J Biol Chem,2005,280(9):8343-8350
[37]Semba I,Nonaka K,Takahashi I,et al.Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2[J].Dev Dyn,2000,217(4):401-414
[38]Pan Q,Yu Y,Chen Q,et al.Sox9,a key transcription factor of bone morphogenetic protein-2-induced chondrogenesis,is activated through BMP pathway and a CCAAT box in the proximal promoter[J].J Cell Physiol,2008,217(1):228-241
[39]Bobick BE,Thornhill TM,Kulyk WM.Fibroblast growth factors2,4,and 8 exert both negative and positive effects on limb,frontonasal,and mandibular chondrogenesis via MEK-ERK activation[J].J Cell Physiol,2007,211(1):233-243
[40]Terao F,Takahashi I,Mitani H,et al.Fibroblast growth factor10 regulates Meckel’s cartilage formation during early mandibular morphogenesis in rats[J].Dev Biol,2011,350(2):337-347