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American Journal of Medical Genetics.... Jan 2020Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic... (Review)
Review
Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.
Topics: Abnormalities, Multiple; Brain Stem; Cerebellum; Eye Abnormalities; Health Personnel; Health Planning Guidelines; Humans; Kidney; Kidney Diseases, Cystic; Liver; Neurodevelopmental Disorders; Retina
PubMed: 31710777
DOI: 10.1002/ajmg.a.61399 -
Prenatal Diagnosis Aug 2019Congenital anomalies of the kidney and urinary tract (CAKUT) constitute 20% of all congenital malformations occurring in one in 500 live births. Worldwide, CAKUT are... (Review)
Review
Congenital anomalies of the kidney and urinary tract (CAKUT) constitute 20% of all congenital malformations occurring in one in 500 live births. Worldwide, CAKUT are responsible for 40% to 50% of pediatric and 7% of adult end-stage renal disease. Pathogenic variants in genes causing CAKUT include monogenic diseases such as polycystic kidney disease and ciliopathies, as well as syndromes that include isolated kidney disease in conjunction with other abnormalities. Prenatal diagnosis most often occurs using ultrasonography; however, further genetic diagnosis may be made using a variety of testing strategies. Family history and pathologic examination can also provide information to improve the ability to make a prenatal diagnosis of CAKUT. Here, we provide a comprehensive overview of genetic considerations in the prenatal diagnosis of CAKUT disorders. Specifically, we discuss monogenic causes of CAKUT, associated ultrasound characteristics, and considerations for genetic diagnosis, antenatal care, and postnatal care.
Topics: Female; Humans; Kidney; Kidney Diseases, Cystic; Pregnancy; Prenatal Diagnosis; Urogenital Abnormalities
PubMed: 31343747
DOI: 10.1002/pd.5536 -
Cells Jan 2023The hepatocyte nuclear factor 1β (HNF1B) gene is involved in the development of specialized epithelia of several organs during the early and late phases of... (Review)
Review
The hepatocyte nuclear factor 1β (HNF1B) gene is involved in the development of specialized epithelia of several organs during the early and late phases of embryogenesis, performing its function mainly by regulating the cell cycle and apoptosis pathways. The first pathogenic variant of HNF1B (namely, R177X) was reported in 1997 and is associated with the maturity-onset diabetes of the young. Since then, more than 230 different HNF1B variants have been reported, revealing a multifaceted syndrome with complex and heterogenous genetic, pathologic, and clinical profiles, mainly affecting the pediatric population. The pancreas and kidneys are the most frequently affected organs, resulting in diabetes, renal cysts, and a decrease in renal function, leading, in 2001, to the definition of HNF1B deficiency syndrome, including renal cysts and diabetes. However, several other organs and systems have since emerged as being affected by HNF1B defect, while diabetes and renal cysts are not always present. Especially, liver involvement has generally been overlooked but recently emerged as particularly relevant (mostly showing chronically elevated liver enzymes) and with a putative relation with tumor development, thus requiring a more granular analysis. Nowadays, HNF1B-associated disease has been recognized as a clinical entity with a broader and more variable multisystem phenotype, but the reasons for the phenotypic heterogeneity are still poorly understood. In this review, we aimed to describe the multifaceted nature of HNF1B deficiency in the pediatric and adult populations: we analyzed the genetic, phenotypic, and clinical features of this complex and misdiagnosed syndrome, covering the most frequent, unusual, and recently identified traits.
Topics: Humans; Child; Hepatocyte Nuclear Factor 1-beta; Kidney; Diabetes Mellitus, Type 2; Kidney Diseases, Cystic; Pancreas
PubMed: 36672242
DOI: 10.3390/cells12020307 -
Pediatric Nephrology (Berlin, Germany) Feb 2011Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease up to the third decade of life. It... (Review)
Review
Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and the most frequent genetic cause of end-stage renal disease up to the third decade of life. It is caused by mutations in 11 different genes, denoted nephrocystins (NPHP1-11, NPHP1L). As an increasing number of these genes are identified, our knowledge of nephronophthisis is changing, thereby improving our understanding of the pathomechanisms in NPHP. Recent publications have described ciliary expression of nephrocystins together with other cystoproteins, such as polycystins 1 and 2 and fibrocystin. These findings have shifted our focus to a pathomechanism involving defects in ciliary function (ciliopathy) and planar cell polarity (PCP). In addition, discoveries of new nephrocystin genes have shown that the disease spectrum of NPHP is much broader than previously anticipated. Different forms of mutations within the same NPHP gene can cause different disease severity. In this review, we highlight the different hypotheses on the pathomechanisms for NPHP and underline the clinical variability of this disease. The clinical spectrum has become even more complex with the possibility of oligogenicity in NPHP.
Topics: Child; Cilia; Genes, Recessive; Humans; Kidney Diseases, Cystic; Mutation; Phenotype
PubMed: 20652329
DOI: 10.1007/s00467-010-1585-z -
American Journal of Physiology. Renal... Dec 2019Glycolytic activity is increased in proliferating cells, leading to the concept that glycolysis could be a therapeutic target in cystic diseases and kidney cancer.... (Review)
Review
Glycolytic activity is increased in proliferating cells, leading to the concept that glycolysis could be a therapeutic target in cystic diseases and kidney cancer. Preclinical studies using the glucose analog 2-deoxy-d-glucose have shown promise; however, inhibiting glycolysis in humans is unlikely to be without risks. While proximal tubules are predominantly aerobic, later segments are more glycolytic. Understanding exactly where and why glycolysis is important in the physiology of the distal nephron is thus crucial in predicting potential adverse effects of glycolysis inhibitors. Live imaging techniques could play an important role in the process of characterizing cellular metabolism in the functioning kidney. The goal of this review is to briefly summarize recent findings on targeting glycolysis in proliferative kidney diseases and to highlight the necessity for future research focusing on glycolysis in the healthy kidney.
Topics: Animals; Antineoplastic Agents; Cell Proliferation; Drug Delivery Systems; Glycolysis; Humans; Kidney Diseases, Cystic; Kidney Neoplasms
PubMed: 31709806
DOI: 10.1152/ajprenal.00460.2019 -
Results and Problems in Cell... 2017Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first... (Review)
Review
Primary cilia are small, antenna-like structures that detect mechanical and chemical cues and transduce extracellular signals. While mammalian primary cilia were first reported in the late 1800s, scientific interest in these sensory organelles has burgeoned since the beginning of the twenty-first century with recognition that primary cilia are essential to human health. Among the most common clinical manifestations of ciliary dysfunction are renal cysts. The molecular mechanisms underlying renal cystogenesis are complex, involving multiple aberrant cellular processes and signaling pathways, while initiating molecular events remain undefined. Autosomal Dominant Polycystic Kidney Disease is the most common renal cystic disease, caused by disruption of polycystin-1 and polycystin-2 transmembrane proteins, which evidence suggests must localize to primary cilia for proper function. To understand how the absence of these proteins in primary cilia may be remediated, we review intracellular trafficking of polycystins to the primary cilium. We also examine the controversial mechanisms by which primary cilia transduce flow-mediated mechanical stress into intracellular calcium. Further, to better understand ciliary function in the kidney, we highlight the LKB1/AMPK, Wnt, and Hedgehog developmental signaling pathways mediated by primary cilia and misregulated in renal cystic disease.
Topics: Animals; Cilia; Humans; Kidney Diseases, Cystic
PubMed: 28409350
DOI: 10.1007/978-3-319-51436-9_11 -
Kidney International Aug 2023Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It is the most... (Review)
Review
Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It is the most common genetic cause of kidney failure in children and young adults. Clinically and genetically heterogeneous, it is caused by variants in ciliary genes, resulting in either an isolated kidney disease or syndromic forms in association with other manifestations of ciliopathy disorders. No curative treatment is currently available. Over the past 2 decades, advances in understanding disease mechanisms have identified several dysregulated signaling pathways, some shared with other cystic kidney diseases. Notably, molecules previously developed to target these pathways have shown promising beneficial effects in orthologous mouse models. In addition to these knowledge-based repurposing approaches, unbiased "in cellulo" phenotypic screens of "repurposing" libraries identified small molecules able to rescue the ciliogenesis defects observed in nephronophthisis conditions. Those compounds appeared to act on relevant pathways and, when tested, showed beneficial nephronophthisis-associated kidney and/or extrarenal defects in mice. In this review, we have summarized those studies that highlight the drug repurposing strategies in the context of a rare disorders, such as nephronophthisis-related ciliopathies, with broad genetic heterogeneity and systemic manifestations but with shared disease mechanisms.
Topics: Animals; Mice; Kidney; Polycystic Kidney Diseases; Kidney Diseases, Cystic; Ciliopathies; Renal Insufficiency; Fibrosis; Cilia
PubMed: 37244473
DOI: 10.1016/j.kint.2023.04.027 -
European Journal of Pediatrics Sep 2012Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment.... (Review)
Review
Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.
Topics: Bardet-Biedl Syndrome; Ciliary Motility Disorders; Genetic Testing; Humans; Kidney Diseases, Cystic; Short Rib-Polydactyly Syndrome
PubMed: 21898032
DOI: 10.1007/s00431-011-1553-z -
Nephrology (Carlton, Vic.) Oct 2018Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children.... (Review)
Review
Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed.
Topics: Adolescent; Adult; Age of Onset; Animals; Disease Progression; Genetic Predisposition to Disease; Humans; Infant; Kidney; Kidney Diseases, Cystic; Kidney Failure, Chronic; Mutation; Phenotype; Prognosis; Risk Factors; Young Adult
PubMed: 29717526
DOI: 10.1111/nep.13393 -
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