LRP4与人类罕见遗传病
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摘要
低密度脂蛋白受体相关蛋白4(low-density lipoprotein receptor-related protein 4,LRP4)在2010年被报道确认为CLS型并指综合征(Cenani-Lenz syndactyly syndrome)的致病基因,相继有文献报道了LRP4的突变会造成17型先天性肌无力症(myasthenic syndrome,congenital 17)和二型硬化性骨病(sclerosteosis 2)。LRP4参与调节经典WNT信号通路和MAPK/JNK信号通路,在神经肌肉接头中与MUSK/AGRIN组成复合物,调节突触后转化。LRP4参与肢端、神经肌肉接头、肾脏、乳腺和牙齿的发育形成,参与骨代谢进程。现将重点介绍LRP4在人类中所引起的3种单基因疾病和从遗传发育角度综述目前关于LRP4的研究进展,对未来深入研究LRP4在脊椎动物早期发育中的功能机制提供一定的参考。
4 gene(LRP4)was found Low-density causative lipoprotein receptor-related Recent protein also identified as Cenani-Lenz syndactyly myasthenic the syndrome syndrome JNK gene in 2010.studies involved the mutations in LRP4 cause signal congenital 17 and sclerosteosis 2.LRP4 is in regulating the canonical binding WNT pathway and MAPK/signal pathway;and in the neuromuscular junction,the LRP4 with MUSK/AGRIN junction,complex mammary regulates glands postsynaptic teeth transformation.LRP4 participates bone in limbs,process.neuromuscular kidneys,and development,as well LRP4 as and the metabolism Here we summarize of three The kinds of will human provide rare a genetic reference diseases caused by latest developmental mechanism and genetic studies early LRP4.review for further studies on the functional of LRP4 in the development of vertebrates.
4 gene(LRP4)was found Low-density causative lipoprotein receptor-related Recent protein also identified as Cenani-Lenz syndactyly myasthenic the syndrome syndrome JNK gene in 2010.studies involved the mutations in LRP4 cause signal congenital 17 and sclerosteosis 2.LRP4 is in regulating the canonical binding WNT pathway and MAPK/signal pathway;and in the neuromuscular junction,the LRP4 with MUSK/AGRIN junction,complex mammary regulates glands postsynaptic teeth transformation.LRP4 participates bone in limbs,process.neuromuscular kidneys,and development,as well LRP4 as and the metabolism Here we summarize of three The kinds of will human provide rare a genetic reference diseases caused by latest developmental mechanism and genetic studies early LRP4.review for further studies on the functional of LRP4 in the development of vertebrates.
引文
[1]Li Y,Cam J,Bu G.Low-density lipoprotein receptor family:endocytosis and signal transduction.Mol Neurobiol,2001,23:53-67
[2]Shen C,Xiong WC,Mei L.LRP4 in neuromuscular junction and bone development and diseases.Bone,2015,80:101-8
[3]Pinson KI,Brennan J,Monkley S,et al.An LDL-receptorrelated protein mediates Wnt signalling in mice.Nature,2000,407:535-8
[4]Tamai K,Semenov M,Kato Y,et al.LDL-receptor-related proteins in Wnt signal transduction.Nature,2000,407:530-5
[5]Nakayama M,Nakajima D,Nagase T,et al.Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening.Genomics,1998,51:27-34
[6]Johnson EB,Hammer RE,Herz J.Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.Hum Mol Genet,2005,14:3523-38
[7]Li Y,Pawlik B,Elcioglu N,et al.LRP4 mutations alter Wnt/β-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.Am J Hum Genet,2010,86:696-706
[8]Leupin O,Piters E,Halleux C,et al.Bone overgrowthassociated mutations in the LRP4 gene impair sclerostin facilitator function.J Biol Chem,2011,286:19489-500
[9]Ohkawara B,Cabrera-Serrano M,Nakata T,et al.LRP4thirdβ-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated Mu SK signaling in a position-specific manner.Hum Mol Genet,2014,23:1856-68
[10]Cenani A,Lenz W.Total syndactylia and total radioulnar synostosis in 2 brothers.A contribution on the genetics of syndactylia.Z Kinderheilkd,1967,101:181-90
[11]Liebenam L.Ueber gleichzeitiges Vorkommen von gliedmassendefekten und osteosklerotischer systemerkrunkung.Z menschliche Vererbungs-und Konstitutionslehre,1938,21:697-70
[12]Borsky AJ.Congenital anomalies of the hand and their surgical treatment.J Pediatrics,1958,53:759
[13]Yelton CL.Certain congenital limb deficiencies occurring in twins and half siblings.Inter-Clinic Inform Bull,1962,1:1-7
[14]Khan TN,Klar J,Ali Z,et al.Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.Eur J Med Genet,2013,56:371-4
[15]Kariminejad A,Stollfu?B,Li Y,et al.Severe CenaniLenz syndrome caused by loss of LRP4 function.Am J Med Genet A,2013,161A:1475-9
[16]Lindy AS,Bupp CP,Mc Gee SJ,et al.Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome.Am J Med Genet A,2014,164A:2391-7
[17]Afzal M,Zaman Q,Kornak U,et al.Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.Eur J Med Genet,2017,60:421-5
[18]Harpf C,Pavelka M,Hussl H.A variant of Cenani-Lenz syndactyly(CLS):review of the literature and attempt of classification.Br J Plast Surg,2005,58:251-7
[19]Simon-Chazottes D,Tutois S,Kuehn M,et al.Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse.Genomics,2006,87:673-7
[20]Weatherbee SD,Anderson KV,Niswander LA.LDLreceptor-related protein 4 is crucial for formation of the neuromuscular junction.Development,2006,133:4993-5000
[21]Ahn Y,Sims C,Logue JM,et al.Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling.Development,2013,140:583-93
[22]Johnson EB,Steffen DJ,Lynch KW,et al.Defective splicing of Megf7/Lrp4,a regulator of distal limb development,in autosomal recessive mulefoot disease.Genomics,2006,88:600-9
[23]Karner CM,Dietrich MF,Johnson EB,et al.Lrp4regulates initiation of ureteric budding and is crucial for kidney formation-a mouse model for Cenani-Lenz syndrome.PLo S One,2010,5:e10418
[24]Tanahashi H,Tian QB,Hara Y,et al.Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis:defects in the pathways of amniotic fluid clearance.Sci Rep,2016,6:20241
[25]Bueno M,Oliván G,Jiménez A,et al.Sclerosteosis in a Spanish male:first report in a person of Mediterranean origin.J Med Genet,1994,31:976-7
[26]Itin PH,KeserüB,Hauser V.Syndactyly/brachyphalangy and nail dysplasias as marker lesions for sclerosteosis.Dermatology,2001,202:259-60
[27]Fijalkowski I,Geets E,Steenackers E,et al.A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone.J Bone Miner Res,2016,31:874-81
[28]Xiong L,Jung JU,Wu H,et al.Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption.Proc Natl Acad Sci USA,2015,112:3487-92
[29]Boudin E,Yorgan T,Fijalkowski I,et al.The Lrp4R1170Q homozygous knock-in mouse recapitulates the bone phenotype of sclerosteosis in humans.J Bone Miner Res,2017,32:1739-49
[30]Kim N,Stiegler AL,Cameron TO,et al.Lrp4 is a receptor for Agrin and forms a complex with Musk.Cell,2008,135:334-42
[31]Zhang B,Luo S,Wang Q,et al.LRP4 serves as a coreceptor of agrin.Neuron,2008,60:285-97
[32]Yumoto N,Kim N,Burden SJ.Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses.Nature,2012,489:438-42
[33]Mak KK,Chen MH,Day TF,et al.Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation.Development,2006,133:3695-707
[34]Solanki I,Parihar P,Parihar MS.Neurodegenerative diseases:From available treatments to prospective herbal therapy.Neurochem Int,2016,95:100-8
[35]Asai N,Ohkawara B,Ito M,et al.LRP4 induces extracellular matrix productions and facilitates chondrocyte differentiation.Biochem Biophys Res Commun,2014,451:302-7
[36]Choi HY,Liu Y,Tennert C,et al.APP interacts with LRP4and agrin to coordinate the development of the neuromuscular junction in mice.Elife,2013,2:e00220
[2]Shen C,Xiong WC,Mei L.LRP4 in neuromuscular junction and bone development and diseases.Bone,2015,80:101-8
[3]Pinson KI,Brennan J,Monkley S,et al.An LDL-receptorrelated protein mediates Wnt signalling in mice.Nature,2000,407:535-8
[4]Tamai K,Semenov M,Kato Y,et al.LDL-receptor-related proteins in Wnt signal transduction.Nature,2000,407:530-5
[5]Nakayama M,Nakajima D,Nagase T,et al.Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening.Genomics,1998,51:27-34
[6]Johnson EB,Hammer RE,Herz J.Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.Hum Mol Genet,2005,14:3523-38
[7]Li Y,Pawlik B,Elcioglu N,et al.LRP4 mutations alter Wnt/β-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.Am J Hum Genet,2010,86:696-706
[8]Leupin O,Piters E,Halleux C,et al.Bone overgrowthassociated mutations in the LRP4 gene impair sclerostin facilitator function.J Biol Chem,2011,286:19489-500
[9]Ohkawara B,Cabrera-Serrano M,Nakata T,et al.LRP4thirdβ-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated Mu SK signaling in a position-specific manner.Hum Mol Genet,2014,23:1856-68
[10]Cenani A,Lenz W.Total syndactylia and total radioulnar synostosis in 2 brothers.A contribution on the genetics of syndactylia.Z Kinderheilkd,1967,101:181-90
[11]Liebenam L.Ueber gleichzeitiges Vorkommen von gliedmassendefekten und osteosklerotischer systemerkrunkung.Z menschliche Vererbungs-und Konstitutionslehre,1938,21:697-70
[12]Borsky AJ.Congenital anomalies of the hand and their surgical treatment.J Pediatrics,1958,53:759
[13]Yelton CL.Certain congenital limb deficiencies occurring in twins and half siblings.Inter-Clinic Inform Bull,1962,1:1-7
[14]Khan TN,Klar J,Ali Z,et al.Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.Eur J Med Genet,2013,56:371-4
[15]Kariminejad A,Stollfu?B,Li Y,et al.Severe CenaniLenz syndrome caused by loss of LRP4 function.Am J Med Genet A,2013,161A:1475-9
[16]Lindy AS,Bupp CP,Mc Gee SJ,et al.Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome.Am J Med Genet A,2014,164A:2391-7
[17]Afzal M,Zaman Q,Kornak U,et al.Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.Eur J Med Genet,2017,60:421-5
[18]Harpf C,Pavelka M,Hussl H.A variant of Cenani-Lenz syndactyly(CLS):review of the literature and attempt of classification.Br J Plast Surg,2005,58:251-7
[19]Simon-Chazottes D,Tutois S,Kuehn M,et al.Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse.Genomics,2006,87:673-7
[20]Weatherbee SD,Anderson KV,Niswander LA.LDLreceptor-related protein 4 is crucial for formation of the neuromuscular junction.Development,2006,133:4993-5000
[21]Ahn Y,Sims C,Logue JM,et al.Lrp4 and Wise interplay controls the formation and patterning of mammary and other skin appendage placodes by modulating Wnt signaling.Development,2013,140:583-93
[22]Johnson EB,Steffen DJ,Lynch KW,et al.Defective splicing of Megf7/Lrp4,a regulator of distal limb development,in autosomal recessive mulefoot disease.Genomics,2006,88:600-9
[23]Karner CM,Dietrich MF,Johnson EB,et al.Lrp4regulates initiation of ureteric budding and is crucial for kidney formation-a mouse model for Cenani-Lenz syndrome.PLo S One,2010,5:e10418
[24]Tanahashi H,Tian QB,Hara Y,et al.Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis:defects in the pathways of amniotic fluid clearance.Sci Rep,2016,6:20241
[25]Bueno M,Oliván G,Jiménez A,et al.Sclerosteosis in a Spanish male:first report in a person of Mediterranean origin.J Med Genet,1994,31:976-7
[26]Itin PH,KeserüB,Hauser V.Syndactyly/brachyphalangy and nail dysplasias as marker lesions for sclerosteosis.Dermatology,2001,202:259-60
[27]Fijalkowski I,Geets E,Steenackers E,et al.A novel domain-specific mutation in a sclerosteosis patient suggests a role of LRP4 as an anchor for sclerostin in human bone.J Bone Miner Res,2016,31:874-81
[28]Xiong L,Jung JU,Wu H,et al.Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption.Proc Natl Acad Sci USA,2015,112:3487-92
[29]Boudin E,Yorgan T,Fijalkowski I,et al.The Lrp4R1170Q homozygous knock-in mouse recapitulates the bone phenotype of sclerosteosis in humans.J Bone Miner Res,2017,32:1739-49
[30]Kim N,Stiegler AL,Cameron TO,et al.Lrp4 is a receptor for Agrin and forms a complex with Musk.Cell,2008,135:334-42
[31]Zhang B,Luo S,Wang Q,et al.LRP4 serves as a coreceptor of agrin.Neuron,2008,60:285-97
[32]Yumoto N,Kim N,Burden SJ.Lrp4 is a retrograde signal for presynaptic differentiation at neuromuscular synapses.Nature,2012,489:438-42
[33]Mak KK,Chen MH,Day TF,et al.Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation.Development,2006,133:3695-707
[34]Solanki I,Parihar P,Parihar MS.Neurodegenerative diseases:From available treatments to prospective herbal therapy.Neurochem Int,2016,95:100-8
[35]Asai N,Ohkawara B,Ito M,et al.LRP4 induces extracellular matrix productions and facilitates chondrocyte differentiation.Biochem Biophys Res Commun,2014,451:302-7
[36]Choi HY,Liu Y,Tennert C,et al.APP interacts with LRP4and agrin to coordinate the development of the neuromuscular junction in mice.Elife,2013,2:e00220
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