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1.
Kidney Int ; 91(5): 1243-1255, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28233610

RESUMO

Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.


Assuntos
Acidose Tubular Renal/genética , Proteína 1 de Troca de Ânion do Eritrócito/genética , Doenças Raras/genética , Insuficiência Renal Crônica/genética , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Estudos Retrospectivos , Adulto Jovem
2.
J Med Genet ; 52(3): 163-74, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25575550

RESUMO

BACKGROUND: Alport syndrome is a clinically heterogeneous, progressive nephropathy caused by mutations in collagen IV genes, namely COL4A3 and COL4A4 on chromosome 2 and COL4A5 on chromosome X. The wide phenotypic variability and the presence of incomplete penetrance suggest that a simple Mendelian model cannot completely explain the genetic control of this disease. Therefore, we explored the possibility that Alport syndrome is under digenic control. METHODS: Using massively parallel sequencing, we identified 11 patients who had pathogenic mutations in two collagen IV genes. For each proband, we ascertained the presence of the same mutations in up to 12 members of the extended family for a total of 56 persons studied. RESULTS: Overall, 23 mutations were found. Individuals with two pathogenic mutations in different genes had a mean age of renal function deterioration intermediate with respect to the autosomal-dominant form and the autosomal-recessive one, in line with molecule stoichiometry of the disruption of the type IV collagen triple helix. CONCLUSIONS: Segregation analysis indicated three possible digenic segregation models: (i) autosomal inheritance with mutations on different chromosomes, resembling recessive inheritance (five families); (ii) autosomal inheritance with mutations on the same chromosome resembling dominant inheritance (two families) and (iii) unlinked autosomal and X-linked inheritance having a peculiar segregation (four families). This pedigree analysis provides evidence for digenic inheritance of Alport syndrome. Clinical geneticists and nephrologists should be aware of this possibility in order to more accurately assess inheritance probabilities, predict prognosis and identify other family members at risk.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Nefrite Hereditária/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Nefrite Hereditária/patologia , Linhagem
3.
Pediatr Nephrol ; 30(6): 931-43, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25480730

RESUMO

BACKGROUND: The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multi-systemic disorder, almost always characterized by the triad of congenital cataract, cognitive and behavioral impairment and a proximal tubulopathy. METHODS: Twenty-eight novel patients with suspected Lowe syndrome were studied. RESULTS: All patients carried OCRL gene defects with mutational hot spots at CpG dinucleotides. Mutations previously unknown in Lowe syndrome were observed in ten of the 28 patients, and carriership was identified in 30.4 % of the mothers investigated. Mapping the exact breakpoints of a complete OCRL gene deletion revealed involvement of several flanking repeat elements. We noted a similar pattern of documented clinically relevant symptoms, and even though the patient cohort comprised relatively young patients, 32 % of these patients already showed advanced chronic kidney disease. Thrombocytopenia was seen in several patients, and hyperosmia and/or hyperacusis were reported recurrently. A p.Asp523Asn mutation in a Polish patient, associated with the typical cerebrorenal spectrum but with late cataract (10 year), was also evident in two milder affected Italian brothers with ocular involvement of similar progression. CONCLUSIONS: We have identified clinical features in 28 patients with suspected Lowe syndrome that had not been recognized in Lowe syndrome prior to our study. We also provide further evidence that OCRL mutations cause a phenotypic continuum with selective and/or time-dependent organ involvement. At least some of these mutants might exhibit a genotype-phenotype correlation.


Assuntos
Mutação , Síndrome Oculocerebrorrenal/diagnóstico , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Catarata/diagnóstico , Catarata/genética , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Ilhas de CpG , Análise Mutacional de DNA , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Heterozigoto , Humanos , Hiperacusia/diagnóstico , Hiperacusia/genética , Índia/epidemiologia , Lactente , Masculino , Síndrome Oculocerebrorrenal/epidemiologia , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prevalência , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Fatores de Tempo , Adulto Jovem
4.
Pediatr Nephrol ; 24(10): 1967-73, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19582483

RESUMO

Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL1 gene, which is usually mutated in patients with Lowe syndrome, have recently been shown to lead to a Dent-like phenotype, called Dent's disease 2. About 25% of Dent's disease patients do not carry CLCN5/OCRL1 mutations. The CLCN4 and SLC9A6 genes have been investigated, but no mutations have been identified. The recent discovery of a novel mediator of renal amino acid transport, collectrin (the TMEM27 gene), may provide new insight on the pathogenesis of Dent's disease. We studied 31 patients showing a phenotype resembling Dent's disease but lacking any CLCN5 mutations by direct sequencing of the OCRL1 and TMEM27 genes. Five novel mutations, L88X, P161HfsX167, F270S, D506N and E720D, in the OCRL1 gene, which have not previously been reported in patients with Dent's or Lowe disease, were identified among 11 patients with the classical Dent's disease phenotype. No TMEM27 gene mutations were discovered among 26 patients, 20 of whom had an incomplete Dent's disease phenotype. Our findings confirm that OCRL1 is involved in the functional defects characteristic of Dent's disease and suggest that patients carrying missense mutations in exons where many Lowe mutations are mapped may represent a phenotypic variant of Lowe syndrome.


Assuntos
Canais de Cloreto/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Nefropatias/genética , Glicoproteínas de Membrana/genética , Monoéster Fosfórico Hidrolases/genética , Análise Mutacional de DNA , Humanos , Masculino , Mutação , Síndrome Oculocerebrorrenal/genética , Fenótipo , Reação em Cadeia da Polimerase
5.
Pediatr Infect Dis J ; 27(5): 406-12, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18382388

RESUMO

BACKGROUND: Human metapneumovirus (hMPV) is an emerging virus associated with acute respiratory tract infections (ARIs) in young children. OBJECTIVES: To evaluate virologic and clinical features of hMPV infection during 2 consecutive winter-spring seasons. METHODS: Nasal washes were obtained from children younger than 5 years of age hospitalized for ARI. Specimens were tested for hMPV by reverse transcription-polymerase chain reaction. The hMPV F gene amplification products were sequenced, and phylogenetic trees were constructed. RESULTS: A high incidence of hMPV infection (25.3%) was observed during the 2005-2006 winter-spring season, whereas a much lower rate of infection (4.7%) during the following season was found. Phylogenetic analysis revealed that, during the 2 seasons, 60.4% of the hMPV detected were A2a, 22.9% were A2b, 4.2% were B1, and 12.5% were B2. hMPV A1 strains were not detected in any tested specimen. Clinical diagnosis was bronchiolitis in 57.1%; pneumonia in 25%; and a upper respiratory tract illness in 17.8%. Bronchiolitis was more frequent in children less than 1 year of age (80%) than in children more than 1 year of age (30.8%) (P < 0.05). When hMPV was found frequently, the hMPV spread overlapped with that of respiratory syncytial virus (RSV) and hMPV/RSV coinfections were common events (19 of 39; 48.7%). hMPV/RSV-coinfected children developed pneumonia more frequently than hMPV-infected patients (57.9% versus 20%) but no differences in disease severity (gauged by duration of hospitalization and requirement of oxygen) were observed. CONCLUSIONS: These results provide further evidence of the importance of hMPV as a pathogen associated with ARI in young children. Involvement of hMPV/RSV coinfection in cases of pneumonia is suspected.


Assuntos
Metapneumovirus/isolamento & purificação , Infecções por Paramyxoviridae/virologia , Infecções Respiratórias/virologia , Fatores Etários , Bronquiolite/virologia , Pré-Escolar , Comorbidade , Feminino , Genótipo , Humanos , Incidência , Lactente , Masculino , Metapneumovirus/classificação , Metapneumovirus/genética , Cavidade Nasal/virologia , Líquido da Lavagem Nasal , Infecções por Paramyxoviridae/epidemiologia , Infecções por Paramyxoviridae/fisiopatologia , Filogenia , Pneumonia/virologia , RNA Viral/genética , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/epidemiologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Homologia de Sequência
6.
Hum Mutat ; 20(1): 78, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12112667

RESUMO

The SLC12A3 gene encodes the thiazide-sensitive Na-Cl co-transporter (NCCT) expressed in the apical membrane of the distal convoluted tubule of the kidney. Inactivating mutations of this gene are responsible for Gitelman syndrome (GS), a disorder inherited as an autosomal recessive trait. We searched for SLC12A3 gene mutations in 21 Italian patients with the clinical and biochemical features of GS (hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria, and the absence of nephrocalcinosis). All coding regions with their intron-exon boundaries were analyzed using PCR and SSCP techniques followed by sequencing analysis. We identified 21 different mutations evenly distributed throughout the gene without any mutation hot-spot. Fifteen are novel variants, including 12 missense mutations, one deletion, one deletion-insertion and one splice site mutation: R158Q, T163M, W172R, G316V, G374V, G463E, A464T, S615W, V677M, R852S, R958G, C985Y, 2114-2120delACCAAGT, 2144-2158delGCCTTCTACTCGGATinsTG, and 531-2A>G.


Assuntos
Alcalose/genética , Proteínas de Transporte/genética , Hipopotassemia/genética , Receptores de Droga , Simportadores , Alcalose/sangue , Alcalose/urina , Cálcio/urina , DNA/química , DNA/genética , Humanos , Hipopotassemia/sangue , Hipopotassemia/urina , Itália , Magnésio/sangue , Mutação , Mutação de Sentido Incorreto , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNA , Deleção de Sequência , Simportadores de Cloreto de Sódio , Membro 3 da Família 12 de Carreador de Soluto , Síndrome
7.
Ital J Pediatr ; 40: 45, 2014 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-24887148

RESUMO

Neutropenia encompasses a family of neutropenic disorders, both permanent and intermittent, ranging from severe (<500 neutrophils/mm(3)) to mild (500-1500 neutrophils/mm(3)), which may also affect other organ systems such as the pancreas, central nervous system, heart, muscle and skin. Neutropenia can lead to life-threatening pyogenic infections whose severity is roughly inversely proportional to the circulating neutrophil counts.When neutropenia is detected, an attempt should be made to establish the etiology, and to distinguish acquired forms (the most frequent, including post viral neutropenia and autoimmune neutropenia) and congenital forms (rare disorders) that may be either isolated or part of a complex rare genetic disease. We report on a male patient initially diagnosed with isolated neutropenia who later turned out to be affected with Barth syndrome, a rare complex inherited disorder.


Assuntos
Anormalidades Múltiplas , Cardiomiopatias/diagnóstico , Transtornos do Crescimento/diagnóstico , Neutropenia/diagnóstico , Aciltransferases , Síndrome de Barth/diagnóstico , Síndrome de Barth/genética , Cardiomiopatias/genética , DNA/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Ecocardiografia , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Humanos , Recém-Nascido , Masculino , Mutação , Radiografia Torácica , Fatores de Transcrição/genética
8.
Kidney Int ; 65(5): 1598-603, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15086897

RESUMO

BACKGROUND: Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown. METHODS: Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation. RESULTS: Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic. CONCLUSION: This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Nefrite Hereditária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Genes Dominantes , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Nefrite Hereditária/etiologia , Nefrite Hereditária/patologia , Linhagem , Fenótipo
9.
J Am Soc Nephrol ; 14(5): 1278-86, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12707396

RESUMO

A total of 179 children with sporadic nephrotic syndrome were screened for podocin mutations: 120 with steroid resistance, and 59 with steroid dependence/frequent relapses. Fourteen steroid-resistant patients presented homozygous mutations that were associated with early onset of proteinuria and variable renal lesions, including one case with mesangial C3 deposition. Single mutations of podocin were found in four steroid-resistant and in four steroid-dependent; five patients had the same mutation (P20L). Among these, two had steroid/cyclosporin resistance, two had steroid dependence, and one responded to cyclosporin. The common variant R229Q of podocin, recently associated with late-onset focal segmental glomerulosclerosis, had an overall allelic frequency of 4.2% versus 2.5% in controls. To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively. Immunohistochemistry with anti-podocin antibodies revealed markedly decreased expression of the protein in their kidneys. All carriers of heterozygous coding podocin mutation or R229Q were screened for nephrin mutation that was found in heterozygosity associated with R229Q in one patient. Finally, podocin loss of heterozygosity was excluded in one heterozygous child by characterizing cDNA from dissected glomeruli. These data outline the clinical features of sporadic nephrotic syndrome due to podocin mutations (homozygous and heterozygous) in a representative population with broad phenotype, including patients with good response to drugs. The pathogenetic implication of single podocin defects per se in proteinuria must be further investigated in view of the possibility that detection of a second mutation could have been missed. A suggested alternative is the involvement of other gene(s) or factor(s).


Assuntos
Proteínas de Membrana/genética , Proteínas dos Microfilamentos , Síndrome Nefrótica/genética , Actinina/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Glomerulosclerose Segmentar e Focal/genética , Heterozigoto , Homozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Síndrome Nefrótica/epidemiologia , Fenótipo , Proteínas/genética , Proteinúria/epidemiologia , Proteinúria/genética
10.
Pediatr Nephrol ; 18(12): 1229-35, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14593522

RESUMO

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D(-)STEC(- )recovered normal renal function compared with 65%-76% of D(+)STEC(+), D(+)STEC(-) and D(-)STEC(+ )patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D(-) but STEC(+) patients have a significantly better prognosis.


Assuntos
Síndrome Hemolítico-Urêmica/epidemiologia , Adolescente , Idade de Início , Doenças do Sistema Nervoso Central/complicações , Criança , Pré-Escolar , Estudos de Coortes , Diarreia/epidemiologia , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/metabolismo , Feminino , Síndrome Hemolítico-Urêmica/patologia , Humanos , Lactente , Itália/epidemiologia , Contagem de Leucócitos , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Toxina Shiga/metabolismo , Análise de Sobrevida , Resultado do Tratamento
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