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Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation
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نویسنده
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grampa v. ,delous m. ,zaidan m. ,odye g. ,thomas s. ,elkhartoufi n. ,filhol e. ,niel o. ,silbermann f. ,lebreton c. ,collardeau-frachon s. ,rouvet i. ,alessandri j.-l. ,devisme l. ,dieux-coeslier a. ,cordier m.-p. ,capri y. ,khung-savatovsky s. ,sigaudy s. ,salomon r. ,antignac c. ,gubler m.-c. ,benmerah a. ,terzi f. ,attié-bitach t. ,jeanpierre c. ,saunier s.
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منبع
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plos genetics - 2016 - دوره : 12 - شماره : 3
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چکیده
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Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium,a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. in order to identify novel genes whose mutations would cause severe developmental ciliopathies,>500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. nek8/nphp9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia,situs inversus,cardiopathy with hypertrophic septum and bile duct paucity. these cases highlight a genotype-phenotype correlation,with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs,respectively. functional analyses of nek8 mutations in patient fibroblasts and mimcd3 cells showed that these mutations differentially affect ciliogenesis,proliferation/apoptosis/dna damage response,as well as epithelial morphogenesis. notably,missense mutations exacerbated some of the defects due to nek8 loss of function,highlighting their likely gain-of-function effect. we also showed that nek8 missense and loss-of-function mutations differentially affect the regulation of the main hippo signaling effector,yap,as well as the expression of its target genes in patient fibroblasts and renal cells. yap imbalance was also observed in enlarged spheroids of nek8-invalidated renal epithelial cells grown in 3d culture,as well as in cystic kidneys of jck mice. moreover,co-injection of nek8 mo with wt or mutated nek8-gfp rna in zebrafish embryos led to shortened dorsally curved body axis,similar to embryos injected with human yap rna. finally,treatment with verteporfin,an inhibitor of yap transcriptional activity,partially rescued the 3d spheroid defects of nek8-invalidated cells and the abnormalities of nek8-overexpressing zebrafish embryos. altogether,our study demonstrates that nek8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the hippo pathway. © 2016 grampa et al.
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آدرس
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inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, inserm u1151,cnrs umr8253,paris descartes—sorbonne paris cité university,necker-enfants malades institute,mechanisms and therapeutic strategies of chronic kidney diseases,necker hospital,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, paris descartes—sorbonne paris cité university,imagine institute,paris,france,inserm umr1163,laboratory of embryology and genetics of congenital malformations,paris, France, paris descartes—sorbonne paris cité university,imagine institute,paris,france,inserm umr1163,laboratory of embryology and genetics of congenital malformations,paris,france,department of genetics,ap-hp,necker hospital,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris,france,department of pediatric nephrology,ap-hp,robert debré hospital,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, paris descartes—sorbonne paris cité university,imagine institute,paris,france,inserm umr1163,laboratory of intestinal immunity,paris, France, department of pathology,hospices civils de lyon,chu de lyon,lyon, France, cellular biotechnology department and biobank,hospices civils de lyon,chu de lyon,lyon, France, chu de la réunion saint-denis/saint-pierre,la réunion, France, anatomopathological department,chru lille,university hospital,lille, France, department of clinical genetics,chru lille,lille, France, department of genetics,femme mère-enfant hospital,university of lyon 1,bron, France, department of genetics,chu robert-debré,paris, France, fetal pathology department,chu robert-debré,paris, France, multidisciplinary department of prenatal diagnosis,la timone children’s hospital,marseille, France, paris descartes—sorbonne paris cité university,imagine institute,paris,france,department of pediatric nephrology,ap-hp,necker hospital,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris,france,department of genetics,ap-hp,necker hospital,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, inserm u1151,cnrs umr8253,paris descartes—sorbonne paris cité university,necker-enfants malades institute,mechanisms and therapeutic strategies of chronic kidney diseases,necker hospital,paris, France, paris descartes—sorbonne paris cité university,imagine institute,paris,france,inserm umr1163,laboratory of embryology and genetics of congenital malformations,paris,france,department of histology-embryology and cytogenetics,ap-hp,necker hospital,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France, inserm umr1163,laboratory of inherited kidney diseases,necker-enfants malades hospital,paris,france,paris descartes—sorbonne paris cité university,imagine institute,paris, France
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Authors
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