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1.
Lancet ; 403(10433): 1279-1289, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38492578

RESUMO

BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.


Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Insuficiência Renal , Humanos , Taxa de Filtração Glomerular , Rim , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Falência Renal Crônica/etiologia , Radar , Doenças Raras , Sistema de Registros , Insuficiência Renal/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Reino Unido/epidemiologia , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais
2.
Am J Hum Genet ; 103(4): 612-620, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30269812

RESUMO

Joubert syndrome (JBTS) is a genetically heterogeneous autosomal-recessive neurodevelopmental ciliopathy. We investigated further the underlying genetic etiology of Joubert syndrome by studying two unrelated families in whom JBTS was not associated with pathogenic variants in known JBTS-associated genes. Combined autozygosity mapping of both families highlighted a candidate locus on chromosome 10 (chr10: 101569997-109106128, UCSC Genome Browser hg 19), and exome sequencing revealed two missense variants in ARL3 within the candidate locus. The encoded protein, ADP ribosylation factor-like GTPase 3 (ARL3), is a small GTP-binding protein that is involved in directing lipid-modified proteins into the cilium in a GTP-dependent manner. Both missense variants replace the highly conserved Arg149 residue, which we show to be necessary for the interaction with its guanine nucleotide exchange factor ARL13B, such that the mutant protein is associated with reduced INPP5E and NPHP3 localization in cilia. We propose that ARL3 provides a potential hub in the network of proteins implicated in ciliopathies, whereby perturbation of ARL3 leads to the mislocalization of multiple ciliary proteins as a result of abnormal displacement of lipidated protein cargo.


Assuntos
Fatores de Ribosilação do ADP/genética , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Cílios/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação de Sentido Incorreto/genética , Retina/anormalidades , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 10/genética , Exoma/genética , Feminino , Proteínas de Ligação ao GTP/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Transporte Proteico/genética , Adulto Jovem
3.
Proc Natl Acad Sci U S A ; 115(49): 12489-12494, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30446612

RESUMO

Genetic treatments of renal ciliopathies leading to cystic kidney disease would provide a real advance in current therapies. Mutations in CEP290 underlie a ciliopathy called Joubert syndrome (JBTS). Human disease phenotypes include cerebral, retinal, and renal disease, which typically progresses to end stage renal failure (ESRF) within the first two decades of life. While currently incurable, there is often a period of years between diagnosis and ESRF that provides a potential window for therapeutic intervention. By studying patient biopsies, patient-derived kidney cells, and a mouse model, we identify abnormal elongation of primary cilia as a key pathophysiological feature of CEP290-associated JBTS and show that antisense oligonucleotide (ASO)-induced splicing of the mutated exon (41, G1890*) restores protein expression in patient cells. We demonstrate that ASO-induced splicing leading to exon skipping is tolerated, resulting in correct localization of CEP290 protein to the ciliary transition zone, and restoration of normal cilia length in patient kidney cells. Using a gene trap Cep290 mouse model of JBTS, we show that systemic ASO treatment can reduce the cystic burden of diseased kidneys in vivo. These findings indicate that ASO treatment may represent a promising therapeutic approach for kidney disease in CEP290-associated ciliopathy syndromes.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Cerebelo/anormalidades , Éxons/genética , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Proteínas Nucleares/genética , Retina/anormalidades , Adolescente , Animais , Antígenos de Neoplasias , Proteínas de Ciclo Celular , Células Cultivadas , Cerebelo/patologia , Proteínas do Citoesqueleto , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Rim/citologia , Masculino , Camundongos , Mutação , Retina/patologia
4.
BMC Nephrol ; 21(1): 435, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059616

RESUMO

BACKGROUND: PKHD1 is the main genetic cause of autosomal recessive polycystic kidney disease (ARPKD), a hereditary hepato-renal fibrocystic disorder which is the most important cause of end-stage renal disease during early childhood. ARPKD can also present in adulthood with milder phenotypes. In this study, we describe a 24-year-old woman with atypical polycystic kidney, no family history of renal disease and no obvious extra-renal manifestations who was referred for genetic investigation. METHODS: We used a combination of next generation sequencing, Sanger sequencing and RNA and microscopy studies performed on urine-derived renal epithelial cells (URECs) to provide a genetic diagnosis of ARPKD. RESULTS: A next generation sequencing panel of cystic ciliopathy genes allowed the identification of two heterozygous sequence changes in PKHD1 (c.6900C > T; p.(Asn2300=) and c.7964A > C; p.(His2655Pro)). The pathogenicity of the synonymous PKHD1 variant is not clear and requires RNA studies, which cannot be carried out efficiently on RNA extracted from proband blood, due to the low expression levels of PKHD1 in lymphocytes. Using URECs as a source of kidney-specific RNA, we show that PKHD1 is alternatively spliced around exon 43, both in control and proband URECs. The variant p.(Asn2300=) shifts the expression ratio in favour of a shorter, out-of-frame transcript. To further study the phenotypic consequence of these variants, we investigated the ciliary phenotype of patient URECs, which were abnormally elongated and presented multiple blebs along the axoneme. CONCLUSIONS: We confirm the power of URECs as a tool for functional studies on candidate variants in inherited renal disease, especially when the expression of the gene of interest is restricted to the kidney and we describe, for the first time, ciliary abnormalities in ARPKD patient cells.


Assuntos
Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Alelos , Análise Mutacional de DNA/métodos , Células Epiteliais , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Rim/diagnóstico por imagem , Masculino , Linhagem , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Reação em Cadeia da Polimerase , Tomografia Computadorizada por Raios X , Urina , Adulto Jovem
5.
Hum Mol Genet ; 26(23): 4657-4667, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973549

RESUMO

Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganized primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinase inhibition (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognized convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Cerebelo/anormalidades , Cílios/patologia , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/patologia , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/patologia , Morfolinas/uso terapêutico , Purinas/uso terapêutico , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Pré-Escolar , Cílios/efeitos dos fármacos , Cílios/genética , Cílios/metabolismo , Ciliopatias/tratamento farmacológico , Ciliopatias/genética , Ciliopatias/metabolismo , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Proteínas do Citoesqueleto , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Masculino , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem , Doenças Renais Policísticas/genética , Cultura Primária de Células , Retina/metabolismo , Retina/patologia , Roscovitina , Transdução de Sinais
6.
Proc Natl Acad Sci U S A ; 111(27): 9893-8, 2014 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-24946806

RESUMO

Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically.


Assuntos
Doenças Cerebelares/metabolismo , Anormalidades do Olho/metabolismo , Proteínas Hedgehog/metabolismo , Doenças Renais Císticas/congênito , Retina/anormalidades , Transdução de Sinais , Anormalidades Múltiplas , Animais , Antígenos de Neoplasias , Proteínas de Ciclo Celular , Cerebelo/anormalidades , Proteínas do Citoesqueleto , Imunofluorescência , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/terapia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Retina/metabolismo
7.
Kidney Int Rep ; 9(7): 2067-2083, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39081723

RESUMO

Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR. Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered). We assessed ethnicity and socioeconomic status in the following: (i) prevalent RaDaR patients receiving KRT compared with patients with eligible rare disease diagnoses receiving KRT in the UKRR, (ii) patients recruited to RaDaR compared with all eligible unrecruited patients at 2 renal centers, and (iii) the age-stratified ethnicity distribution of RaDaR patients with autosomal dominant polycystic kidney disease (ADPKD) was compared to that of the English census. Results: We found evidence of disparities in ethnicity and social deprivation in recruitment to RaDaR; however, these were not consistent across comparisons. Compared with either adults recruited to RaDaR or the English population, children recruited to RaDaR were more likely to be of Asian ethnicity (17.3% vs. 7.5%, P-value < 0.0001) and live in more socially deprived areas (30.3% vs. 17.3% in the most deprived Index of Multiple Deprivation (IMD) quintile, P-value < 0.0001). Conclusion: We observed no evidence of systematic biases in recruitment of patients into RaDaR; however, the data provide empirical evidence of negative economic and social consequences (across all ethnicities) experienced by families with children affected by rare kidney diseases.

8.
Front Nephrol ; 2: 984165, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-37674994

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is a cause of end-stage kidney disease (ESKD). The vasopressin V2-receptor antagonist tolvaptan has been shown within randomized clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a Northeast England cohort of adult ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real-world clinic setting. Other inclusion criteria involved a pre-treatment decline in greater than 2.5 ml/min/1.73m2/year based on readings for a 3 year period, and ability to tolerate and maintain tolvaptan treatment for at least 12 months. We calculated based on eGFR slopes, predicted time to reach ESKD with and without tolvaptan therapy. The cohort of patients included 21 from the Northeast of England. The mean rate of eGFR decline prior to treatment was -6.02 ml/min/1.73m2/year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.47 ml/min/1.73m2/year, gaining a mean 8 years and 4 months delay to reach ESKD. The majority of patients (n=19) received and tolerated full dose tolvaptan (90 mg/30 mg). The real-life use of tolvaptan gave a dramatic improvement in eGFR slopes, much more than previously reported in clinical studies. These effects may be in part due to careful patient identification, selection and inclusion of patients who were able to tolerate tolvaptan therapy, excellent compliance with medication and a "tolvaptan clinic" effect where great personal care was given to these patients.

9.
Kidney Int ; 80(9): 986-991, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21814174

RESUMO

Peritonitis remains a common clinical problem for patients on peritoneal dialysis (PD). There are, however, retrospective studies with historical controls that suggest that biocompatible PD solutions may reduce the rates of peritonitis. We conducted a randomized controlled study comparing the use of biocompatible and conventional solutions, accumulating over 7000 patient-months experience. We included peritonitis episodes from patients who discontinued PD during the follow-up period. The study was powered to detect a reduction in the peritonitis rate of over half in the 267 randomized patients in demographically similar groups. There were no intergroup differences in PD technique survival irrespective of whether the outcome was censored for death. Peritonitis-free survival was 26.7 months using conventional compared to 23.1 months using biocompatible PD solutions. The peritonitis rates were also not statistically different when measured in patient-months. Thus, despite the finding of non-randomized studies suggesting benefits of the biocompatible PD solutions, we could not detect any clinically significant advantages in terms of technique survival or peritonitis. Although our study is the largest randomized study comparing different PD solutions to date, we do not exclude the possibility that our results are a consequence of the lack of statistical power. Meta-analysis of randomized control trials in this field is essential.


Assuntos
Materiais Biocompatíveis/administração & dosagem , Soluções para Diálise/administração & dosagem , Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua/métodos , Peritonite/prevenção & controle , Materiais Biocompatíveis/efeitos adversos , Distribuição de Qui-Quadrado , Soluções para Diálise/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/mortalidade , Londres , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Diálise Peritoneal Ambulatorial Contínua/mortalidade , Peritonite/etiologia , Peritonite/mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Diálise Renal , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
10.
Sci Rep ; 9(1): 10828, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346239

RESUMO

Joubert syndrome (JBTS) is an incurable multisystem ciliopathy syndrome. The most commonly mutated gene in JBTS patients with a cerebello-retinal-renal phenotype is CEP290 (alias JBTS5). The encoded CEP290 protein localises to the proximal end of the primary cilium, in the transition zone, where it controls ciliary protein composition and signalling. We examined primary cilium structure and composition in fibroblast cells derived from homozygous and compound heterozygous JBTS5 patients with nonsense mutations in CEP290 and show that elongation of cilia, impaired ciliogenesis and ciliary composition defects are typical features in JBTS5 cells. Targeted skipping of the mutated exon c.5668 G > T using antisense oligonucleotide (ASO) therapy leads to restoration of CEP290 protein expression and functions at the transition zone in homozygous and compound heterozygous JBTS5 cells, allowing a rescue of both cilia morphology and ciliary composition. This study, by demonstrating that targeted exon skipping is able to rescue ciliary protein composition defects, provides functional evidence for the efficacy of this approach in the treatment of JBTS.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Cílios/metabolismo , Ciliopatias/genética , Éxons , Anormalidades do Olho/genética , Fibroblastos/metabolismo , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/metabolismo , Cerebelo/metabolismo , Ciliopatias/metabolismo , Anormalidades do Olho/metabolismo , Humanos , Doenças Renais Císticas/metabolismo , Transporte Proteico , Retina/metabolismo
11.
Eur J Hum Genet ; 26(12): 1791-1796, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30002499

RESUMO

The majority of multi-exon genes undergo alternative splicing to produce different mRNA transcripts and this may occur in a tissue-specific manner. Assessment of mRNA transcripts isolated from blood samples may sometimes be unhelpful in determining the affect on function of putative splice-site variants affecting kidney-specific mRNA transcripts. Here we present data demonstrating the power of using human urine-derived renal epithelial cells (hUREC) as a source of kidney RNA. We report clinical and molecular genetic data from three affected cases from two families all with end-stage renal disease by 15 years of age. In both families, heterozygous variants which are predicted to effect function in NPHP3 were found on one allele, in combination with a synonymous SNV (c.2154C>T; p.Phe718=), 18 base pairs from the exon-intron boundary within exon 15 of NPHP3. The only mRNA transcript amplified from wild-type whole blood showed complete splicing out of exon 15. Urine samples obtained from control subjects and the father of family 2, who carried the synonymous SNV variant, were therefore used to culture hUREC and allowed us to obtain kidney-specific mRNA. Control kidney mRNA showed retention of exon 15, while the mRNA from the patient's father confirmed evidence of a heterozygous alternate splicing of exon 15 of NPHP3. Analysis of RNA derived from hUREC allows for a comparison of kidney-specific and whole-blood RNA transcripts and for assessment of the effect on function of putative splice variants leading to end-stage kidney disease.


Assuntos
Células Epiteliais/metabolismo , Falência Renal Crônica/genética , Polimorfismo de Nucleotídeo Único , Splicing de RNA , Urina/citologia , Adolescente , Células Cultivadas , Criança , Feminino , Testes Genéticos/métodos , Humanos , Falência Renal Crônica/patologia , Cinesinas/genética , Cinesinas/metabolismo , Cultura Primária de Células/métodos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Front Pediatr ; 5: 287, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29379777

RESUMO

Nephronophthisis (NPHP) is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required.

13.
F1000Res ; 6: 669, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28690834

RESUMO

Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases. When transcripts containing these changes are generated, they are usually rapidly removed by the cell through the process of nonsense-mediated decay. Here we discuss observed changes in transcripts of the centrosomal protein CEP290 resulting not from degradation, but from changes in exon usage. We also comment on a landmark paper (Drivas et al. Sci Transl Med. 2015) where modelling this process of exon usage may be used to predict disease severity in CEP290 ciliopathies, and how understanding this process may potentially be used for therapeutic benefit in the future.

14.
Case Rep Nephrol ; 2017: 4653267, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29181208

RESUMO

The complications of autosomal dominant polycystic kidney disease (ADPKD) include cyst rupture and haemorrhage leading to loin pain and frank haematuria. Risk factors include large kidney volume, hypertension, and renal impairment. We present a case of a young male who, following trauma to the kidney, had a life threatening bleed from his polycystic kidney. The case was initially treated with fluid resuscitation and blood transfusion but necessitated radiological embolization of bleeding source to control the blood loss. We review the risk factors and management of cyst haemorrhage in patients with ADPKD. Contact sports should be avoided as cyst rupture can lead to severe life threatening haemorrhage.

15.
Biol Trace Elem Res ; 171(1): 48-53, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26364956

RESUMO

Micronutrients and trace elements have been identified to play an important role in the development of Parkinson's disease (PD). In our previous study, we observed that prolidase activity is associated with oxidative stress and progression of PD. In present study, we aimed to study the association of prolidase-associated trace elements, such as Co, Mn, Ni, and Zn in the plasma of patients with PD by inductively coupled plasma spectrometry. Plasma levels of Co, Mn, and Ni were significantly increased, whereas plasma levels of Zn was significantly decreased (all P < 0.05) in the patients with PD than healthy controls. Plasma prolidase activity was not correlated to its associated trace elements in PD. A positive, linear, and significant correlation was observed between age and Co, and Mn, and Ni while negative and non-significant between age and status of Zn in the patients. Co, Mn, and Ni were continually elevated with increase in age as well as duration of disease in the patients with PD, whereas status of Zn was continually decreased. Thus, the study concluded that trace elements Co, Ni, and Mn status were increased and Zn status was decreased in the plasma of patients with PD. It is also concluded that elevated Co, Mn, and Ni has been associated with progression of Parkinson's disease.


Assuntos
Dipeptidases/sangue , Doença de Parkinson/sangue , Oligoelementos/sangue , Adulto , Idoso , Dipeptidases/metabolismo , Ativação Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo
16.
Parkinsons Dis ; 2015: 598028, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26347150

RESUMO

Prolidase deficiency has been related to mental retardation and oxidative stress. The study aimed to observe plasma prolidase activity (PPA), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) in patients with Parkinson's disease (PD). 240 subjects with PD and 150 healthy volunteers were considered as cases and controls, respectively. PPA, TOS, TAS, and OSI were measured spectrophotometrically. PPA and TAS in cases were more significantly decreased than controls (P < 0.01), while TOS and OSI were significantly increased (P < 0.001). In cases, nonsignificant, positive correlation was observed between PPA and TOS and OSI while significant, negative correlation was observed between PPA and TAS (P = 0.047). PPA in cases was nonsignificantly decreased with increased duration of PD (P = 0.747) while TAS was significantly decreased (P < 0.001) and TOS and OSI were significantly increased (P < 0.001). It was observed that higher age groups had decreased PPA, and TAS and increased TOS and OSI compared to lower age groups in cases. In summary, patients with PD have decreased PPA and increased oxidative stress compared to healthy volunteers. PPA was associated with oxidative stress markers in patients with PD. Decreased PPA and TAS and increased TOS and OSI were associated with progression of disease and higher age.

17.
Clin Kidney J ; 8(4): 453-5, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26251716

RESUMO

Mutations in CYP24A1, encoding the vitamin D 24-hydroxlase enzyme, are known to cause a range of clinical phenotypes and presentations including idiopathic infantile hypercalcaemia and adult-onset nephrocalcinosis and nephrolithiasis. In the context of raised or borderline high serum calcium levels, suppressed PTH and persistently elevated 1,25 dihydroxy vitamin D levels, this rare condition should be considered. We present a case where this biochemical pattern was seen and mutations in CYP24A1 were confirmed. We were able to successfully control serum calcium levels and reduce urinary calcium excretion by treatment with low-dose fluconazole, which inhibits vitamin D-synthesizing enzymes (including 25-hydroxylases and 1-α-hydroxylase) thereby reducing levels of 1,25-dihydroxy vitamin D.

18.
Clin Kidney J ; 8(1): 113-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25713721

RESUMO

End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail-patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened.

19.
J Clin Invest ; 125(9): 3657-66, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26301811

RESUMO

Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes.


Assuntos
Antígenos de Neoplasias/metabolismo , Cerebelo/anormalidades , Dano ao DNA , Rim/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Retina/anormalidades , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Animais , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular , Linhagem Celular , Centríolos/genética , Centríolos/metabolismo , Centríolos/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Proteínas do Citoesqueleto , Replicação do DNA , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Humanos , Rim/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Retina/metabolismo , Retina/patologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
20.
J Pediatr Genet ; 3(2): 103-14, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27625867

RESUMO

Nephronophthisis (NPHP) is a childhood cystic kidney disease, which almost invariably leads to end-stage renal disease in those affected. Recognition and diagnosis requires clinical suspicion, biochemical evaluation, renal imaging and historically, renal biopsy. Modern molecular genetics now allows a diagnosis to be made in a significant proportion of cases. Mutations in NPHP1 account for 20% of cases, but the disease is genetically heterogeneous with at least 20 different genes associated with NPHP. Recent developments in the fields of genetics and proteomics have led to increased understanding of the underlying pathogenetic defects. Almost all NPHP genes encode proteins, which localize to the primary cilia, basal body and centrosome. NPHP is a therefore considered to be a ciliopathy, and can be part of a broad spectrum of clinical disease that includes extra-renal manifestations including retinal degeneration, cerebellar ataxia, liver fibrosis and situs inversus. In this review, we discuss the historical descriptions of NPHP in the context of more recent developments in our understanding of this disease.

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