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American Journal of Kidney Diseases :... Mar 2021Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play... (Review)
Review
Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play important roles in tissue development and signal transduction, with mutations in ciliary-associated proteins resulting in a group of diseases collectively known as ciliopathies. Many of these mutations manifest as renal ciliopathies, characterized by kidney dysfunction resulting from aberrant cilia or ciliary functions. This group of overlapping and genetically heterogeneous diseases includes polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome as the main focus of this review. Renal ciliopathies are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity, downstream of dysregulated ciliary-dependent signaling. Due to cystic-associated kidney injury and systemic inflammation, cases result in kidney failure requiring dialysis and transplantation. Of the handful of pharmacologic treatments available, none are curative. It is important to determine the molecular mechanisms that underlie the involvement of the primary cilium in cyst initiation, expansion, and progression for the development of novel and efficacious treatments. This review updates research progress in defining key genes and molecules central to ciliogenesis and renal ciliopathies.
Topics: Abnormalities, Multiple; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Bardet-Biedl Syndrome; Cerebellum; Chaperonins; Cilia; Ciliary Motility Disorders; Ciliopathies; Cytoskeletal Proteins; Encephalocele; Eye Abnormalities; Humans; Kidney Diseases, Cystic; Leber Congenital Amaurosis; Membrane Proteins; Microtubule-Associated Proteins; Optic Atrophies, Hereditary; Polycystic Kidney Diseases; Proteins; Retina; Retinitis Pigmentosa; TRPP Cation Channels
PubMed: 33039432
DOI: 10.1053/j.ajkd.2020.08.012 -
Journal of Mother and Child Mar 2022Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the... (Review)
Review
Joubert syndrome (JS; MIM PS213300) is a rare genetic autosomal recessive disease characterized by cerebellar vermis hypoplasia, a distinctive malformation of the cerebellum and the so-called "molar tooth sign." Other characteristic features are hypotonia with lateral ataxia, intellectual disability/mental retardation, oculomotor apraxia, retinal dystrophy, abnormalities in the respiratory system, renal cysts, hepatic fibrosis, and skeletal changes. Such pleiotropic characteristics are typical of many disorders involving primary cilium aberrations, providing a significant overlap between JS and other ciliopathies such as nephronophthisis, Meckel syndrome, and Bardet-Biedl syndrome. This review will describe some characteristics of JS associated with changes in 35 genes, and will also address subtypes of JS, clinical diagnosis, and the future of therapeutic developments.
Topics: Humans; Cerebellum; Abnormalities, Multiple; Eye Abnormalities; Retina; Polycystic Kidney Diseases; Intellectual Disability
PubMed: 36803942
DOI: 10.34763/jmotherandchild.20222601.d-22-00034 -
The New England Journal of Medicine Apr 2011Diverse developmental and degenerative single-gene disorders such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, the Bardet–Biedl syndrome, the... (Review)
Review
Diverse developmental and degenerative single-gene disorders such as polycystic kidney disease, nephronophthisis, retinitis pigmentosa, the Bardet–Biedl syndrome, the Joubert syndrome, and the Meckel syndrome may be categorized as ciliopathies — a recent concept that describes diseases characterized by dysfunction of a hairlike cellular organelle called the cilium. Most of the proteins that are altered in these single-gene disorders function at the level of the cilium–centrosome complex, which represents nature’s universal system for cellular detection and management of external signals. Cilia are microtubule-based structures found on almost all vertebrate cells. They originate from a basal body, a modified centrosome, which is the organelle that forms the spindle poles during mitosis. The important role that the cilium–centrosome complex plays in the normal function of most tissues appears to account for the involvement of multiple organ systems in ciliopathies. In this review, we consider the role of the cilium in disease.
Topics: Centrosome; Cilia; Ciliary Motility Disorders; Eye Diseases; Genotype; Hedgehog Proteins; Humans; Kidney Diseases; Mutation; Phenotype; Signal Transduction; Ultrasonography
PubMed: 21506742
DOI: 10.1056/NEJMra1010172 -
Annual Review of Genomics and Human... Aug 2022The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human... (Review)
Review
The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. Primary cilia are near-ubiquitous, microtubule-based organelles that play crucial roles in development and homeostasis. Protruding from the cell, these cellular antennae sense diverse signals and mediate Hedgehog and other critical signaling pathways. Ciliary dysfunction causes many human conditions termed ciliopathies, which range from multiple congenital malformations to adult-onset single-organ failure. Research on the genetics of the JS-MKS-NPH spectrum has spurred extensive functional work exploring the broadly important role of primary cilia in health and disease. This functional work promises to illuminate the mechanisms underlying JS-MKS-NPH in humans, identify therapeutic targets across genetic causes, and generate future precision treatments.
Topics: Abnormalities, Multiple; Cerebellum; Child; Cilia; Ciliary Motility Disorders; Ciliopathies; Encephalocele; Eye Abnormalities; Hedgehog Proteins; Humans; Kidney Diseases, Cystic; Polycystic Kidney Diseases; Retina; Retinitis Pigmentosa
PubMed: 35655331
DOI: 10.1146/annurev-genom-121321-093528 -
Cold Spring Harbor Perspectives in... Mar 2017Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With... (Review)
Review
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and, currently, mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dimorphism, and, in some cases, laterality defects, and congenital heart disease. Mutations in the same gene can give rise to diverse phenotypes depending on the mutated allele. At the same time, there is broad phenotypic overlap between different monogenic genes. The identification of monogenic causes of ciliopathies has furthered the understanding of molecular mechanism and cellular pathways involved in the pathogenesis.
Topics: Animals; Cilia; Genes, Recessive; Humans; Kidney Diseases; Models, Biological; Mutation
PubMed: 27793968
DOI: 10.1101/cshperspect.a028191 -
Genome Biology Nov 2016Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically...
BACKGROUND
Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.
RESULTS
We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their "mutation load" beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.
CONCLUSIONS
Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.
Topics: Alleles; Cilia; Ciliary Motility Disorders; Ciliopathies; DNA Mutational Analysis; Encephalocele; Genetic Association Studies; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Mutation; Phenotype; Polycystic Kidney Diseases; Retina; Retinitis Pigmentosa
PubMed: 27894351
DOI: 10.1186/s13059-016-1099-5 -
Current Opinion in Pediatrics Apr 2015Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most common genetic disorders causing end-stage renal disease (ESRD) in... (Review)
Review
PURPOSE OF REVIEW
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most common genetic disorders causing end-stage renal disease (ESRD) in children and adolescents. NPHP is a genetically heterogenous disorder with 20 identified genes. NPHP occurs as an isolated kidney disease, but approximately 15% of NPHP patients have additional extrarenal symptoms affecting other organs [e.g. eyes, liver, bones and central nervous system (CNS)]. The pleiotropy in NPHP is explained by the finding that almost all NPHP gene products share expression in primary cilia, a sensory organelle present in most mammalian cells. If extrarenal symptoms are present in addition to NPHP, these disorders are classified as NPHP-related ciliopathies (NPHP-RC). This review provides an update about recent advances in the field of NPHP-RC.
RECENT FINDINGS
The identification of novel disease-causing genes has improved our understanding of the pathomechanisms contributing to NPHP-RC. Multiple interactions between different NPHP-RC gene products have been published and outline the interconnectivity of the affected proteins and shared pathways.
SUMMARY
The significance of recently identified genes for NPHP-RC is discussed and the complex role and interaction of NPHP proteins in ciliary function and cellular signalling pathways is highlighted.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Child; Cilia; Cytoskeletal Proteins; Genes, Recessive; Humans; Kidney; Kidney Diseases, Cystic; Kidney Failure, Chronic; Membrane Proteins; Mutation; Phenotype; Signal Transduction
PubMed: 25635582
DOI: 10.1097/MOP.0000000000000194