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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 686-689, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302911

RESUMO

OBJECTIVE: To explore the pathogenesis of two fetuses from one family affected with Joubert syndrome (JS). METHODS: Whole exome sequencing was employed to screen potential mutations in both fetuses. Suspected mutations were verified by Sanger sequencing. Impact of intronic mutations on DNA transcription was validated by cDNA analysis. RESULTS: Two novel TCTN1 mutations, c.342-8A>G and c.1494+1G>A, were identified in exons 2 and 12, respectively.cDNA analysis confirmed the pathogenic nature of both mutations with interference of normal splicing resulting in production of truncated proteins. CONCLUSION: The genetic etiology of the family affected with JS has been identified.Above findings have enriched the mutation spectrum of TCTN1gene and facilitated understanding of the genotype-phenotype correlation of JS.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades do Olho/diagnóstico , Humanos , Doenças Renais Císticas/diagnóstico , Mutação , Linhagem , Sequenciamento Completo do Exoma
2.
Hum Genet ; 138(10): 1105-1115, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31230195

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.


Assuntos
Colágeno Tipo IV/genética , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Rim/anormalidades , Mutação , Fenótipo , Sistema Urinário/anormalidades , Alelos , Substituição de Aminoácidos , Biologia Computacional/métodos , Análise Mutacional de DNA , Bases de Dados Genéticas , Evolução Molecular , Feminino , Estudos de Associação Genética , Loci Gênicos , Genômica/métodos , Heterozigoto , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Navegador , Sequenciamento Completo do Exoma
3.
Arch Endocrinol Metab ; 63(3): 250-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066763

RESUMO

OBJECTIVE: To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. SUBJECTS AND METHODS: We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. RESULTS: We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. CONCLUSION: The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).


Assuntos
Nefropatias Diabéticas/genética , Fator 1-beta Nuclear de Hepatócito/genética , Hiperglicemia/genética , Doenças Renais Císticas/genética , Mutação , Adulto , Brasil , Estudos de Coortes , Nefropatias Diabéticas/complicações , Deleção de Genes , Humanos , Hiperglicemia/complicações , Doenças Renais Císticas/complicações , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético/genética
4.
Clin Nephrol ; 92(2): 89-94, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31131822

RESUMO

OBJECTIVE: Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease. Its onset is obscure, and its early clinical manifestations and pathological changes lack specificity, which makes clinical diagnosis difficult. At present, as many as 90 genetic alterations can result in NPH, which exhibits significant genetic heterogeneity. Therefore, high-throughput sequencing technology provides an effective method to identify and characterize novel NPH pathogenic genes when compared to Sanger sequencing. This study summarizes the gene mutations and clinical data of whole exome sequencing, which was used to diagnose 5 NPH patients to improve the understanding of the causative genes and clinical phenotypes of NPH. MATERIALS AND METHODS: The clinical manifestations, laboratory examination indexes, and imaging data of 5 patients of NPH were reported. Whole exome sequencing was performed in 5 children, and the causative genes and mutation sites were analyzed by bioinformatics and genetics. The mutation sites were verified in children and their parents using Sanger direct sequencing. RESULTS: Among the 5 patients (3 male and 2 female), 2 patients had infantile NPH, and 3 patients had juvenile NPH. The 2 infantile NPH patients were characterized by the onset of liver dysfunction accompanied by hypertension and left ventricular change, and the renal function progressed to end-stage renal disease (ESRD) after 7 months and 9 months, respectively. The 2 cases of infantile NPH had NPHP3 mutations, with one carrying compound heterozygous mutations (c.1358A>G, c.2369A>G) and the other simultaneously carrying a c.1174C>T IVS26-3A>G cleavage site mutation from the father and a nonsense mutation (p.392R>X, 939) from the mother. The 2 juvenile NPH children had entered ESRD at the onset of the disease, including 1 patient with Joubert syndrome. The 2 patients with juvenile NPH had frameshift mutations (c.1583 to 1596: deletion) and homozygous point mutations (7 c.640G>T) of the NPHP1 gene. In addition, another patient with frequent urination and nocturia resulting in stage CKD3 renal function had a complex heterozygous mutation of the NPHP2 gene (c.2686G>A, c.1943A>G). The urine A1MU/creatinine and urinary transferrin increased in all 5 patients without hematuria. CONCLUSION: Whole exome sequencing identified the causative genes of NPH in 5 children. In NPH children with NPHP3 gene mutations, renal functional damage was characterized by early onset and rapid progression to ESRD, often accompanied by liver dysfunction and hypertension.


Assuntos
Doenças Renais Císticas/congênito , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Criança , Pré-Escolar , China , Feminino , Heterozigoto , Homozigoto , Humanos , Lactente , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Falência Renal Crônica/etiologia , Cinesina/genética , Masculino , Proteínas de Membrana/genética , Mutação/genética , Fenótipo , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
5.
Dev Biol ; 448(1): 36-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695685

RESUMO

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.


Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologia
6.
Medicine (Baltimore) ; 97(50): e13531, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30558011

RESUMO

RATIONALE: Ciliopathies is a group of clinically and genetically overlapping disorders due to cilia abnormalities and multiple organ systems are involved in. PATIENT CONCERNS: We present a young female patient who showed renal function impairment, Caroli syndrome (CS), liver cirrhosis, polycystic ovarian syndrome, and multiple subcutaneous cysts. DIAGNOSES: The patient was diagnosed with ciliopathy according to the clinical manifestations and whole-genome sequencing. INTERVENTIONS: She received treatment of intravenous albumin, polyene phosphatidyl choline, furosemide, and antisterone. OUTCOMES: The patient showed clinical improvement in her edema and liver tests, and ultrasonography revealed that the ascites had disappeared. Unfortunately, the edema relapsed a year later. The patient received the same treatment as before, and there was clinical improvement of the edema. Since the family cannot afford liver and kidney transplantation, the patient only accepted symptomatic treatment. LESSONS: Polycystic ovarian syndrome and multiple subcutaneous cysts have never before been reported to be associated with ciliopathy. This finding could remind doctors to consider the possibility of ciliopathy disease for patients suffering from similar conditions. In addition, the phenotype of the patient differs from those of patients reported with the same mutations, which also reminds doctors that the clinical manifestation of a given mutation may show patient-specific differences. This case report extends the phenotypic spectrum of ciliopathy, and these findings might represent a new ciliopathy syndrome, which could facilitate the diagnosis of ciliopathies.


Assuntos
Doença de Caroli/genética , Ciliopatias/genética , Doenças Renais Císticas/genética , Cirrose Hepática/genética , Síndrome do Ovário Policístico/genética , Adolescente , Doença de Caroli/complicações , Ciliopatias/complicações , Feminino , Humanos , Doenças Renais Císticas/complicações , Cirrose Hepática/complicações , Mutação , Fenótipo , Síndrome do Ovário Policístico/complicações
7.
J Hum Genet ; 63(8): 935-939, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29695797

RESUMO

Biallelic pathogenic variants in PIBF1 have been identified as one of the genetic etiologies of Joubert syndrome. We report a two-year-old girl with global developmental delay, facial dysmorphism, hypotonia, enlarged cystic kidneys, molar tooth sign, and thinning of corpus callosum. A novel homozygous 36-bp insertion in PIBF1 (c.1181_1182ins36) was identified by exome sequencing as the likely cause of her condition. This is the second publication demonstrating the cause and effect relationship between PIBF1 and Joubert syndrome.


Assuntos
Anormalidades Múltiplas/genética , Alelos , Pareamento de Bases/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutagênese Insercional/genética , Proteínas da Gravidez/genética , Retina/anormalidades , Fatores Supressores Imunológicos/genética , Anormalidades Múltiplas/diagnóstico por imagem , Sequência de Bases , Cerebelo/diagnóstico por imagem , Pré-Escolar , Anormalidades do Olho/diagnóstico por imagem , Feminino , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Retina/diagnóstico por imagem
8.
Clin Nephrol ; 89(3): 223-228, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29162218

RESUMO

We investigated a 25-year-old Japanese man who had polycystic kidneys and end-stage renal failure without a positive family history. Ultrasonography revealed enlarged kidneys with increased echogenicity and multiple cystic lesions. MRI showed replacement of both kidneys by cystic lesions without definite walls. Renal biopsy demonstrated interstitial fibrosis, especially at the corticomedullary junction. The residual tubular system showed starfish-like disruption. Tubules with cystic dilation were mainly the distal loop of Henle and the distal tubules since immunohistochemical staining was positive for cytokeratin 7 (the distal loop of Henle and the distal tubule) and Tamm-Horsfall protein (the distal loop of Henle), while being negative for aquaporin 3 (the collecting duct) and CD10 (proximal tubule). Comprehensive genetic analysis identified compound heterozygous missense mutations of NPHP4 with autosomal recessive inheritance since his asymptomatic parents each had a single heterozygous missense mutation of NPHP4. In conclusion, MRI and immunohistochemical analysis of renal biopsy specimens may be useful for evaluation of this disease.
.


Assuntos
Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/patologia , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/patologia , Imagem por Ressonância Magnética , Adulto , Humanos , Imuno-Histoquímica , Doenças Renais Císticas/genética , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Proteínas/genética
9.
Nephrology (Carlton) ; 23(4): 371-376, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28124483

RESUMO

AIM: The TTC21B gene is now known as causative of nephronophthisis-related ciliopathies (NPHP-RC). We reported two Chinese paediatric cases with end-stage renal disease and other phenotypes caused by the TTC21B gene mutations. METHODS: The clinical features of Chinese paediatric cases with NPHP-RC were summarized. Mutation analysis of the TTC21B gene was performed using next-generation sequencing. RESULTS: The two cases both had nephrotic proteinuria, renal failure, hypertension and abnormal liver function (or hepatic fibrosis). One case also presented situs inversus and short phalanges. They developed end-stage renal disease (ESRD) at 1 year old and 8 years old, respectively, when renal pathology both showed focal segmental glomerular sclerosis (FSGS) with tubulointerstitial lesions including interstitial fibrosis and atrophic tubules. Three novel disease-causing TTC21B mutations were identified. One case carried homozygous mutation c.2211 + 3A > G, while the other case carried compound heterozygous mutations c.1552 T > C (p.C518R) and c.1456dupA (p.R486KfsX22). CONCLUSION: Mutations in TTC21B cause a range of ciliopathy phenotypes in humans. We identified 3 novel TTC21B mutations in two Chinese paediatric cases that both presented end-stage renal disease and other different features. This is the first TTC21B mutations ever reported in China.


Assuntos
Ciliopatias/genética , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Criança , China , Ciliopatias/complicações , Ciliopatias/diagnóstico , Análise Mutacional de DNA/métodos , Progressão da Doença , Evolução Fatal , Feminino , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/etiologia , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Lactente , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico , Falência Renal Crônica/etiologia , Masculino , Fenótipo , Fatores de Tempo
10.
Genet Med ; 20(2): 223-233, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28771248

RESUMO

PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4.9% were candidates for di-/oligogenicity, harboring heterozygous RDVs in two or more genes, compared with 4.2-8% in controls (P = 0.66-0.21). Based on Exome Aggregation Consortium (ExAC) allele frequencies, the probability of cumulating RDVs in any two JBTS genes is 9.3%. We found no support for triallelism, as no unaffected siblings carried the same biallelic RDVs as their affected relative. Sixty percent of individuals sharing identical causal RDVs displayed phenotypic discordance. Although 38% of affected individuals harbored RDVs in addition to the causal mutations, their presence did not correlate with phenotypic severity.ConclusionOur data offer little support for triallelism or digenicity/oligogenicity as clinically relevant inheritance modes in JBTS. While phenotypic discordance supports the existence of genetic modifiers, identifying clinically relevant modifiers remains challenging.


Assuntos
Genes Recessivos , Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Variação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Cerebelo/anormalidades , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Genes Modificadores , Estudos de Associação Genética/métodos , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Modelos Genéticos , Herança Multifatorial , Mutação , Fenótipo , Retina/anormalidades
11.
Eur J Hum Genet ; 25(12): 1324-1334, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29255182

RESUMO

ARL13B encodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellectual disability, ataxia, and ocular abnormalities. Here we report a novel homozygous missense variant c.[223G>A] (p.(Gly75Arg) in the ARL13B gene, which was identified by whole-exome sequencing of a trio from a consanguineous family with multiple-affected individuals suffering from intellectual disability, ataxia, ocular defects, and epilepsy. The same variant was also identified in a second family. We saw a striking difference in the severity of ataxia between affected male and female individuals in both families. Both ARL13B and ARL13B-c.[223G>A] (p.(Gly75Arg) expression rescued the cilia length and Shh defects displayed by Arl13b hennin (null) cells, indicating that the variant did not disrupt either ARL13B function. In contrast, ARL13B-c.[223G>A] (p.(Gly75Arg) displayed a marked loss of ARL3 guanine nucleotide-exchange factor activity, with retention of its GTPase activities, highlighting the correlation between its loss of function as an ARL3 guanine nucleotide-exchange factor and Joubert syndrome.


Assuntos
Fatores de Ribosilação do ADP/genética , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação com Perda de Função , Retina/anormalidades , Fatores de Ribosilação do ADP/metabolismo , Anormalidades Múltiplas/diagnóstico , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Células Cultivadas , Criança , Anormalidades do Olho/diagnóstico , Feminino , Guanosina Trifosfato/metabolismo , Homozigoto , Humanos , Doenças Renais Císticas/diagnóstico , Masculino , Camundongos , Mutação de Sentido Incorreto , Linhagem
12.
Clin J Am Soc Nephrol ; 12(12): 1974-1983, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29146700

RESUMO

BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ciliopatias/genética , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Fenótipo , Adolescente , Anemia/genética , Antígenos de Neoplasias/genética , Proteínas de Ligação a Calmodulina/genética , Proteínas de Transporte/genética , Criança , Ciliopatias/complicações , Estudos Transversais , Feminino , Taxa de Filtração Glomerular/genética , Homozigoto , Humanos , Rim/diagnóstico por imagem , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Falência Renal Crônica/fisiopatologia , Cinesina/genética , Estudos Longitudinais , Masculino , Proteínas de Neoplasias/genética , Doenças do Sistema Nervoso/genética , Poliúria/genética , Proteínas/genética , Ultrassonografia , Adulto Jovem
13.
Clin J Am Soc Nephrol ; 12(12): 1962-1973, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29146704

RESUMO

BACKGROUND AND OBJECTIVES: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. RESULTS: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). CONCLUSIONS: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Cerebelo/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idade de Início , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Criança , Pré-Escolar , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico por imagem , Feminino , Genótipo , Humanos , Lactente , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Falência Renal Crônica/etiologia , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Rim Displásico Multicístico/complicações , Rim Displásico Multicístico/diagnóstico por imagem , Rim Displásico Multicístico/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Rim Policístico Autossômico Recessivo/genética , Estudos Prospectivos , Proteínas/genética , Retina/diagnóstico por imagem , Retina/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
14.
Am J Med Genet A ; 173(12): 3231-3237, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29052317

RESUMO

Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium. Here, we report the detailed clinical phenotypes of two sisters with a novel homozygous variant in INPP5E (NM_019892.4: c.1565G>C, NP_063945.2: p.Gly552Ala), expanding the phenotype associated with Joubert syndrome type 1. Expression studies using patient-derived fibroblasts showed changes in mRNA and protein levels. Analysis of fibroblasts from patients revealed that a significant number of cells had shorter or no cilia, indicating defects in ciliogenesis, and cilia maintenance.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Ciliopatias/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Monoéster Fosfórico Hidrolases/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Adolescente , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Cílios/patologia , Ciliopatias/diagnóstico , Ciliopatias/patologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/patologia , Feminino , Fibroblastos/patologia , Homozigoto , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/patologia , Imagem por Ressonância Magnética , Mutação , Linhagem , Fenótipo , Retina/diagnóstico por imagem , Retina/patologia , Adulto Jovem
15.
Am J Hum Genet ; 101(4): 552-563, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28965847

RESUMO

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Cerebelo/anormalidades , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Genes Recessivos , Proteínas Hedgehog/metabolismo , Doenças Renais Císticas/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Retina/anormalidades , Anormalidades Múltiplas/patologia , Doenças do Desenvolvimento Ósseo/patologia , Células Cultivadas , Cerebelo/patologia , Criança , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Doenças Renais Císticas/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Retina/patologia , Análise de Sequência de DNA , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Proteína Gli3 com Dedos de Zinco
16.
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 , 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 , 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
17.
Nephrology (Carlton) ; 22(10): 818-820, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28921755

RESUMO

We present a case of a foetal sonographic finding of hyper-echogenic kidneys, which led to a strategic series of genetic tests and identified a homozygous mutation (c.424C > T, p. R142*) in the NPHP3 gene. Our study provides a rare presentation of NPHP3-related ciliopathy and adds to the mutation spectrum of the gene, being the first one from Pakistani population. With a thorough literature review, it also advocates for molecular assessment of ciliopathies to improve risk estimate for future pregnancies, and identify predisposed asymptomatic carriers.


Assuntos
Ciliopatias/genética , Códon sem Sentido , Homozigoto , Doenças Renais Císticas/genética , Cinesina/genética , Aborto Induzido , Adulto , Ciliopatias/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Idade Gestacional , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Fenótipo , Gravidez , Ultrassonografia Pré-Natal
18.
Development ; 144(20): 3686-3697, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28893945

RESUMO

The Zfp423/ZNF423 gene encodes a 30-zinc-finger transcription factor involved in key developmental pathways. Although null Zfp423 mutants develop cerebellar malformations, the underlying mechanism remains unknown. ZNF423 mutations are associated with Joubert Syndrome, a ciliopathy causing cerebellar vermis hypoplasia and ataxia. ZNF423 participates in the DNA-damage response (DDR), raising questions regarding its role as a regulator of neural progenitor cell cycle progression in cerebellar development. To characterize in vivo the function of ZFP423 in neurogenesis, we analyzed allelic murine mutants in which distinct functional domains are deleted. One deletion impairs mitotic spindle orientation, leading to premature cell cycle exit and Purkinje cell (PC) progenitor pool deletion. The other deletion impairs PC differentiation. In both mutants, cell cycle progression is remarkably delayed and DDR markers are upregulated in cerebellar ventricular zone progenitors. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time strengthens the emerging notion that an impaired DDR may be a key factor in the pathogenesis of JS and other ciliopathies.


Assuntos
Ciclo Celular , Proteínas de Ligação a DNA/fisiologia , Células-Tronco Neurais/citologia , Neurônios/citologia , Células de Purkinje/citologia , Fatores de Transcrição/fisiologia , Anormalidades Múltiplas/genética , Alelos , Animais , Diferenciação Celular , Divisão Celular , Proliferação de Células , Cerebelo/anormalidades , Dano ao DNA , Anormalidades do Olho/genética , Deleção de Genes , Doenças Renais Císticas/genética , Camundongos , Mutação , Domínios Proteicos , Retina/anormalidades , Fuso Acromático/metabolismo , Dedos de Zinco
19.
Nat Cell Biol ; 19(10): 1178-1188, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28846093

RESUMO

Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.


Assuntos
Anormalidades Múltiplas/patologia , Cerebelo/anormalidades , Cílios/patologia , Ciliopatias/patologia , Anormalidades do Olho/patologia , Doenças Renais Císticas/patologia , Microscopia de Fluorescência/métodos , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Cílios/metabolismo , Ciliopatias/genética , Ciliopatias/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Processamento de Imagem Assistida por Computador , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Mutação , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Fenótipo , Retina/metabolismo , Retina/patologia , Transdução de Sinais , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Processos Estocásticos , Adulto Jovem
20.
Clin Nephrol ; 88(9): 162-166, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28766492

RESUMO

Heterozygous hepatocyte nuclear factor-1-α gene (HNF1A) mutations are the most common cause of maturity-onset diabetes of the young (MODY), but they rarely involve extrahepatic manifestations. Renal cysts and diabetes syndrome can be caused by HNF1B mutations. No association between MODY3 and Dandy-Walker variants (DWV) has been reported. HNF1A mutations might be responsible for renal malformations. In a Japanese girl with glycosuria, developmental delay, mental retardation, renal cysts, and DWV, the HNF1B gene had no mutations. Array comparative genomic hybridization analysis identified a de-novo interstitial 12q24.22-q24.31 deletion of 5.6 Mb encompassing the HNF1A gene, which is compatible with a diagnosis of MODY3. The variety of phenotypes suggests a novel microdeletion syndrome spanning the HNF1A gene. Because HNF1B functions as an HNF1A/HNF1B heterodimer, haploinsufficient HNF1A interacts with a certain HNF1B haplotype. The resulting truncated heterodimer might engender renal cysts. More patients with well-defined deletion within 12q.24.31 must be evaluated to produce a detailed genotype-phenotype correlation and to elucidate this emerging microdeletion syndrome.
.


Assuntos
Síndrome de Dandy-Walker/genética , Diabetes Mellitus Tipo 2/genética , Deleção de Genes , Fator 1-alfa Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Criança , Hibridização Genômica Comparativa , Feminino , Estudos de Associação Genética , Humanos , Mutação
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