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1.
Medicine (Baltimore) ; 99(31): e21438, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756155

RESUMO

RATIONALE: Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene result in a very variable presentation, including maturity onset diabetes of the young (MODY), renal cysts, renal dysplasia, and autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterized by tubular damage, renal fibrosis, and progressive renal dysfunction. PATIENT CONCERNS: A 22-year-old man came to the hospital presenting with hyperglycemia, hyperuricemia and elevated serum creatinine. His urine protein was within the normal range. The ultrasound examination revealed shrunken kidneys with renal cysts. The patient's mother was diagnosed with diabetes mellitus when she was 25 years old. Her laboratory results showed elevated serum creatinine. Her ultrasonography revealed shrunken kidneys with renal cysts and hydronephrosis without kidney stones. The next-generation sequencing revealed that the proband and his mother held the same heterozygous missense mutation (c.530G>A, NM_000458, p.R177Q) in the HNF1B gene. Bioinformatic analyses predicted that the mutation was likely pathogenic. DIAGNOSIS: The patient and his mother were diagnosed as ADTKD and MODY5 due to HNF1B mutation. INTERVENTION: The proband was administered metformin at a dose of 500 mg/day. OUTCOMES: The patient had well-controlled blood glucose levels and a stable renal function at his 12-month follow-up. LESSONS: We should take into account the diagnoses of ADTKD and MODY5 if patients present with early onset diabetes and multiple renal cysts or evidence of renal tubulointerstitial dysplasia, especially those with negative proteinuria results. Genetic testing helps detect the HNF1B gene mutations.


Assuntos
Doenças do Sistema Nervoso Central/genética , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Nefrite Intersticial/genética , Assistência ao Convalescente , Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hiperglicemia/etiologia , Hiperuricemia/etiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Rim/diagnóstico por imagem , Rim/patologia , Rim/fisiopatologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Mutação de Sentido Incorreto , Nefrite Intersticial/complicações , Nefrite Intersticial/patologia , Linhagem , Ultrassonografia/métodos , Adulto Jovem
2.
PLoS One ; 15(6): e0235071, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574212

RESUMO

Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis. The aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with cystic kidney diseases. Next-generation sequencing of genes responsible for the formation of cystic kidneys was performed in 31 unrelated patients with various clinically diagnosed cystic kidney diseases gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one (in case of autosomal recessive inheritance) pathogenic variant was found in 29% of patients (n = 9). The result of NGS correlated with the clinical diagnosis made before the NGS in 55% of patients (n = 17), in the remaining 14 children (45%) the result of NGS revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes. The most common unexpected findings were variants in nephronophthisis (NPHP) genes in children with clinically suspected autosomal recessive polycystic kidney disease (ARPKD, n = 4). Overall, 24 pathogenic or probably pathogenic variants were detected in the PKHD1 gene, 8 variants in the TMEM67 gene, 4 variants in the PKD1 gene, 2 variants in the HNF1B gene and 2 variants in BBS1 and NPHP1 genes, respectively. NGS is a valuable tool in the diagnostics of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 16% (n = 5) of the children.


Assuntos
Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Renais Císticas/genética , Mutação , Rim Policístico Autossômico Recessivo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Pré-Escolar , Proteínas do Citoesqueleto/genética , República Tcheca , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Lactente , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Masculino , Proteínas Associadas aos Microtúbulos/genética , Rim Policístico Autossômico Recessivo/diagnóstico , Receptores de Superfície Celular/genética , Canais de Cátion TRPP/genética
3.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
4.
BMC Med Genet ; 21(1): 84, 2020 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-32306954

RESUMO

BACKGROUND: Nephronophthisis (NPHP) is a rare autosomal recessive inherited disorder with high heterogeneity. The majority of NPHP patients progress to end-stage renal disease (ESRD) within the first three decades of life. As an inherited disorder with highly genetic heterogeneity and clinical presentations, NPHP still poses a challenging task for nephrologists without special training to make a well-judged decision on its precise diagnosis, let alone its mechanism and optimal therapy. CASE PRESENTATION: A Chinese family with NPHP was recruited in current study. The clinical characteristics (including findings from renal biopsy) of NPHP patients were collected from medical records and the potential responsible genes were explored by the whole exome sequencing (WES). A homozygous deletion of NPHP1 (1-20 exons) was found in both affected patients, which was further confirmed by quantitative PCR. CONCLUSIONS: Homozygous full gene deletion of the NPHP1 gene was identified in a Chinese family with NPHP, which was the molecular pathogenic basis of this disorder. Furthermore, identification of the pathogenic genes for those affected patients can help to have a full knowledge on NPHP's molecular mechanism and precise treatment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Adulto , Éxons/genética , Feminino , Deleção de Genes , Homozigoto , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/fisiopatologia , Falência Renal Crônica/fisiopatologia , Masculino , Linhagem , Deleção de Sequência/genética , Sequenciamento Completo do Exoma
5.
Am J Physiol Renal Physiol ; 318(5): F1306-F1312, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308017

RESUMO

Defects in the function of primary cilia are commonly associated with the development of renal cysts. On the other hand, the intact cilium appears to contribute a cystogenic signal whose effectors remain unclear. As integrin-ß1 is required for the cystogenesis caused by the deletion of the polycystin 1 gene, we asked whether it would be similarly important in the cystogenetic process caused by other ciliary defects. We addressed this question by investigating the effect of integrin-ß1 deletion in a ciliopathy genetic model in which the Ift88 gene, a component of complex B of intraflagellar transport that is required for the proper assembly of cilia, is specifically ablated in principal cells of the collecting ducts. We showed that the renal cystogenesis caused by loss of Ift88 is prevented when integrin-ß1 is simultaneously depleted. In parallel, pathogenetic manifestations of the disease, such as increased inflammatory infiltrate and fibrosis, were also significantly reduced. Overall, our data indicate that integrin-ß1 is also required for the renal cystogenesis caused by ciliary defects and point to integrin-ß1-controlled pathways as common drivers of the disease and as possible targets to interfere with the cystogenesis caused by ciliary defects.


Assuntos
Cílios/metabolismo , Integrina beta1/metabolismo , Doenças Renais Císticas/metabolismo , Rim/metabolismo , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Cílios/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose , Mediadores da Inflamação/metabolismo , Integrina beta1/genética , Rim/patologia , Rim/fisiopatologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/prevenção & controle , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Knockout , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 509-513, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335874

RESUMO

OBJECTIVE: To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transporte Vesicular , Cerebelo/anormalidades , Anormalidades do Olho , Testes Genéticos , Doenças Renais Císticas , Proteínas de Membrana , Diagnóstico Pré-Natal , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Variação Genética , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Gravidez
7.
J Nutr ; 150(5): 1135-1143, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32006016

RESUMO

BACKGROUND: Ex vivo studies suggest that increased renal prostanoids can mediate effects of high-protein (HP) compared with low-protein (LP) diets on normal and diseased kidneys. However, a short-term HP feeding study in normal male rats failed to demonstrate higher renal prostanoids in vivo. OBJECTIVES: The aim of the present study was to investigate whether long-term HP feeding alters renal prostanoids in male and female mice, with and without kidney disease. METHODS: Weanling normal mice (CD1) and mice with kidney disease (CD1-pcy/pcy mice) were fed standard diets with normal protein [NP, 20% of energy (%E)] or HP (35%E) for 13 wk. Renal disease was assessed by histomorphometric analysis of cysts and fibrosis, and measurement of serum urea nitrogen (SUN) and creatinine concentrations. Targeted analysis of renal oxylipins was performed by HPLC-MS/MS. RESULTS: The HP diet increased kidney size and water content of normal kidneys, and worsened disease in CD1-pcy/pcy mice as indicated by higher (P < 0.05) kidney weights (8-31%), water content (8-10%), cyst volume (36-60%), fibrous volume (44-53%), and SUN (47-55%). Diseased compared with normal kidneys had higher (P < 0.05) concentrations of 6 of 11 prostanoids and lower (P < 0.05) concentrations of 33 of 54 other oxylipins. This is consistent with previously known effects of dietary HP and disease effects on the kidney. However, the HP diet did not alter renal prostanoids and other renal oxylipins in either normal or diseased kidneys (P < 0.05), despite having the expected physiological effects on normal and diseased kidneys. This study also showed that females have higher concentrations of renal prostanoids [9 of 11 prostanoids higher (P < 0.05) in females], but lower concentrations of other oxylipins [28 of 54 other oxylipins lower (P < 0.05) in females]. CONCLUSIONS: The effects of HP diets on normal and diseased kidneys in CD1 and CD1-pcy/pcy mice are independent of renal oxylipin alterations.


Assuntos
Dieta Rica em Proteínas/efeitos adversos , Nefropatias/genética , Nefropatias/metabolismo , Rim/química , Oxilipinas/análise , Prostaglandinas/análise , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Genótipo , Rim/patologia , Nefropatias/patologia , Doenças Renais Císticas/congênito , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Masculino , Camundongos , Tamanho do Órgão , Prostaglandina-Endoperóxido Sintases/metabolismo , Fatores Sexuais
8.
BMC Med Genet ; 21(1): 18, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000717

RESUMO

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Criança , Éxons/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Vietnã , Sequenciamento Completo do Exoma
9.
PLoS One ; 15(1): e0221914, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990917

RESUMO

Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited genetic disorders that share a defect in the formation, maintenance or functioning of the primary cilium complex, causing progressive cystic kidney disease and other clinical manifestations. Mutations in centrosomal protein 164 kDa (CEP164), also known as NPHP15, have been identified as a cause of NPHP-RC. Here we have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) to perform immunohistochemistry studies on human embryonic and foetal tissues to determine the expression patterns of CEP164 during development. Notably expression is widespread, yet defined, in multiple organs including the kidney, retina and cerebellum. Murine studies demonstrated an almost identical Cep164 expression pattern. Taken together, these data support a conserved role for CEP164 throughout the development of numerous organs, which, we suggest, accounts for the multi-system disease phenotype of CEP164-mediated NPHP-RC.


Assuntos
Cílios/genética , Ciliopatias/genética , Doenças Renais Císticas/genética , Proteínas dos Microtúbulos/genética , Animais , Cílios/patologia , Ciliopatias/patologia , Modelos Animais de Doenças , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Rim/metabolismo , Rim/patologia , Doenças Renais Císticas/patologia , Camundongos , Retina/metabolismo , Retina/patologia
10.
Neurology ; 94(8): e797-e801, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31969461

RESUMO

OBJECTIVE: To estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort. METHODS: We enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available. RESULTS: We identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41-0.53), 0.41 (95% CI 0.32-0.49), and 0.53 (95% CI 0.45-0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49-1.97), 1.62 (95% CI 1.31-1.99), and 1.80 (95% CI 1.49-2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r 2 = 0.79; p < 0.001). CONCLUSIONS: We estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients' genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.


Assuntos
Anormalidades Múltiplas/epidemiologia , Cerebelo/anormalidades , Anormalidades do Olho/epidemiologia , Doenças Renais Císticas/epidemiologia , Retina/anormalidades , Anormalidades Múltiplas/genética , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Bases de Dados Genéticas , Anormalidades do Olho/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Itália/epidemiologia , Doenças Renais Císticas/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Adulto Jovem
11.
Mol Med Rep ; 21(3): 1115-1124, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31922211

RESUMO

Hereditary nephropathy is a progressive fatal renal disease caused by genetic changes. In this study, genetic screening was used to reveal mutations in a family in Southern China, in which there are two patients with confirmed hereditary nephropathy, who are alive at the time of publication. Imaging tests, including color Doppler ultrasonography and magnetic resonance imaging (MRI), as well as pathological examinations, including hematoxylin­eosin staining, electron microscopy and immunohistochemistry were performed. Target sequencing of nephrosis 2 (NPHS2), wilms tumor 1 (WT1), phospholipase C ε 1 (PLCE1), actinin α 4 (ACTN4), angiotensin I converting enzyme (ACE), uromodulin (UMOD) and nephrocystin 1 (NPHP1) was also carried out. This study indicated that heterozygous genetic variants of NPHS2, WT1, ACTN4, PLCE1 and UMOD found in the patients were gene polymorphisms. A renal biopsy showed sclerosing glomerulonephritis, dilated tubules and lymphocyte/monocyte infiltration in the interstitium of the index patients. Genetic analysis showed vertical transmission of the disease­causing mutations, including a homozygous deletion in NPHP1 and a nonsense mutation in ACE found via PCR­based single nucleotide polymorphism screening. Further network analysis identified direct and indirect co­location genes between NPHP1 and ACE. To conclude, familial adolescent nephronophthisis was diagnosed in two index patients in this study. It is recommended that comprehensive gene mutation screening is used in the diagnosis of complex hereditary diseases.


Assuntos
Família , Doenças Genéticas Inatas , Glomerulonefrite , Doenças Renais Císticas , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Glomerulonefrite/genética , Glomerulonefrite/patologia , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Masculino , Pessoa de Meia-Idade
12.
Gene ; 729: 144229, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706999

RESUMO

Nephronophthisis is an autosomal recessive disease characterized by cystic kidney disease with progression to end-stage kidney disease in children and adolescents with or without extra-renal involvement. It is caused by biallelic pathogenic variants in 19 genes including INVS that encodes a ciliary protein essential for renal development and left-right axis establishment. We report a child with bilateral enlarged, echogenic, polycystic kidneys with end-stage renal disease, anemia and metabolic acidosis caused by biallelic novel pathogenic variants, c.796 + 5G > A and c.1789C > T in INVS. We show that the variant, c.796 + 5G > A disrupts the canonical splicing and nonsense variant, c.1789C > T results in nonsense mediated decay.


Assuntos
Doenças Renais Císticas/genética , Fatores de Transcrição/genética , Pré-Escolar , Códon sem Sentido , Feminino , Frequência do Gene , Variação Genética , Homozigoto , Humanos , Doenças Renais Císticas/metabolismo , Mutação , Sítios de Splice de RNA , Processamento de RNA , Fatores de Transcrição/metabolismo
13.
Clin Dysmorphol ; 29(1): 10-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31577543

RESUMO

With the increasing availability and clinical use of exome and whole-genome sequencing, reverse phenotyping is now becoming common practice in clinical genetics. Here, we report a patient identified through the Wellcome Trust Deciphering Developmental Disorders study who has homozygous pathogenic variants in CC2D2A and a de-novo heterozygous pathogenic variant in KIDINS220. He presents with developmental delay, intellectual disability, and oculomotor apraxia. Reverse phenotyping has demonstrated that he likely has a composite phenotype with contributions from both variants. The patient is much more mildly affected than those with Joubert Syndrome or Spastic paraplegia, intellectual disability, nystagmus, and obesity, the conditions associated with CC2D2A and KIDINS220 respectively, and therefore, contributes to the phenotypic variability associated with the two conditions.


Assuntos
Anormalidades Múltiplas , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento , Anormalidades do Olho , Deficiência Intelectual , Doenças Renais Císticas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Cerebelo/patologia , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Homozigoto , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Masculino , Retina/patologia , Retina/fisiopatologia
14.
Proc Natl Acad Sci U S A ; 117(2): 1113-1118, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31879347

RESUMO

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Anormalidades do Olho/genética , Genes Modificadores , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Predisposição Genética para Doença/genética , Nefropatias , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
15.
Dev Cell ; 51(6): 759-774.e5, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31846650

RESUMO

Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia function, are characterized by axonal tract malformations. However, little is known about how cilia-driven signaling regulates axonal growth and connectivity. We demonstrate that the deletion of related JSRD genes, Arl13b and Inpp5e, in projection neurons leads to de-fasciculated and misoriented axonal tracts. Arl13b deletion disrupts the function of its downstream effector, Inpp5e, and deregulates ciliary-PI3K/AKT signaling. Chemogenetic activation of ciliary GPCR signaling and cilia-specific optogenetic modulation of downstream second messenger cascades (PI3K, AKT, and AC3) commonly regulated by ciliary signaling receptors induce rapid changes in axonal dynamics. Further, Arl13b deletion leads to changes in transcriptional landscape associated with dysregulated PI3K/AKT signaling. These data suggest that ciliary signaling acts to modulate axonal connectivity and that impaired primary cilia signaling underlies axonal tract defects in JSRD.


Assuntos
Anormalidades Múltiplas/metabolismo , Axônios/metabolismo , Cerebelo/anormalidades , Cílios/metabolismo , Anormalidades do Olho/genética , Doenças Renais Císticas/metabolismo , Retina/anormalidades , Anormalidades Múltiplas/genética , Animais , Cerebelo/metabolismo , Modelos Animais de Doenças , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/genética , Camundongos , Mutação/genética , Neurogênese/fisiologia , Retina/metabolismo
16.
Tohoku J Exp Med ; 249(1): 29-32, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31534065

RESUMO

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that is characterized by primary ciliary dysfunction (ciliopathy) and progresses to end-stage kidney disease (ESKD) during the second decade of life (juvenile and adolescent NPHP) or before the age of 3 years (infantile NPHP). Here we describe the case of an infant with NPHP who carries a homozygous mutation in SDCCAG8 (also called NPHP10 or BBS16) that encodes SDCCAG8 (serologically defined colon cancer antigen 8). SDCCAG8 is localized at the centrioles of both renal epithelial cells and retinal photoreceptor cells. A mutation in SDCCAG8 is also associated with Bardet-Biedl syndrome (BBS), characterized by NPHP, obesity, polydactyly, and rod-cone dystrophy. A 2-year-old boy was referred to our hospital due to kidney dysfunction of unknown etiology; the patient presented with delayed development and opsoclonus but did not exhibit the clinical characteristics of BBS. Histological findings such as dilatation of tubules and irregular thickness of tubular basement membrane confirmed the diagnosis of NPHP. Four months after referral, the patient's renal function was rapidly deteriorated, and emergency peritoneal dialysis was initiated. Next-generation sequencing (NGS) was performed, showing that the patient carries a homozygous four-base-pair deletion in SDCCAG8 (c.849_852delTTTG, p.Cys283Ter). The patient's parents were also found to be heterozygous for this loss-of-function mutation. To the best of our knowledge, the present patient is the first case of biopsy-proven infantile NPHP with a homozygous SDCCAG8 mutation. We conclude that NGS is extremely useful in the identification of SDCCAG8-related NPHP as a cause of sudden-onset ESKD during infancy.


Assuntos
Autoantígenos/genética , Doenças Renais Císticas/congênito , Mutação/genética , Proteínas de Neoplasias/genética , Sequência de Bases , Pré-Escolar , Homozigoto , Humanos , Rim/patologia , Doenças Renais Císticas/genética , Masculino
17.
Saudi J Kidney Dis Transpl ; 30(4): 964-968, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464256

RESUMO

A 19-year-old female with a learning difficulty, ataxia, and nystagmus was referred to our clinic with advanced chronic kidney disease. Her renal biopsy revealed features of nephronophthisis (NPHP). Magnetic resonance imaging of the brain showed "molar tooth sign." The clinical picture was consistent with Joubert syndrome (JS). Two of her siblings were subsequently found to have a similar condition. Genomic material from the patient, her twin sister, and later on from parents was analyzed for deletion/duplication mutations in the NPHP1 gene using multiplex ligation-dependent probe amplification. No genetic defect was discerned. However, applying the emerging "Next-Generation Sequencing (NGS)" method, we identified a novel c.5704G>T mutation in exon 41 of the CEP290 gene on chromosome 12q21. The identification of this novel mutation, that is, highly likely to be pathogenic was compatible with the diagnosis of JS. This mutation may be included in screening and diagnostic panel. NGS provides an excellent screening method for genetic testing.


Assuntos
Anormalidades Múltiplas/genética , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA/métodos , Anormalidades do Olho/genética , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Renais Císticas/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/terapia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/terapia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/terapia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Arábia Saudita , Adulto Jovem
18.
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
19.
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
20.
Stem Cell Res ; 38: 101480, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31202121

RESUMO

Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, characterized by congenital cerebellar and brainstem defects, belonging to the group of disorders known as ciliopathies, which are caused by mutations in genes encoding proteins of the primary cilium and basal body. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a homozygous missense mutation (c.2168G > A) in AHI1, the first gene to be associated with JS, were produced using a virus-free protocol.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transporte Vesicular , Cerebelo/anormalidades , Anormalidades do Olho , Homozigoto , Células-Tronco Pluripotentes Induzidas , Doenças Renais Císticas , Mutação de Sentido Incorreto , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adulto , Linhagem Celular , Cerebelo/metabolismo , Cerebelo/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Masculino , Retina/metabolismo , Retina/patologia
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