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1.
J Hum Genet ; 65(4): 355-362, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31959872

RESUMO

Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin ß2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin ß2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.


Assuntos
Membrana Basal Glomerular , Laminina , Mutação de Sentido Incorreto , Síndromes Miastênicas Congênitas , Síndrome Nefrótica , Distúrbios Pupilares , Splicing de RNA , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Membrana Basal Glomerular/metabolismo , Membrana Basal Glomerular/patologia , Humanos , Lactente , Laminina/biossíntese , Laminina/genética , Masculino , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/metabolismo , Síndromes Miastênicas Congênitas/patologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Domínios Proteicos , Distúrbios Pupilares/genética , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/patologia
5.
Pediatr Nephrol ; 22(2): 232-6, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17043884

RESUMO

An awareness of the triggers of relapse is critical for the control of steroid-dependent, frequently relapsing nephrotic syndrome (SDFRNS). We have investigated the triggers, usually described as 'episodes', to such relapses within a temporal context. Thirty-five patients with SDFRNS were analyzed retrospectively. A total of 442 relapses occurred in 2499 patient-months. The relapses were classified into two groups: those with episodes (E+) and those without episodes (E-). There were 135 E+ relapses and 296 E- relapses. The common cold was the most common episode (52%) of E+ relapse, followed by school events (18%). These E+ relapses occurred almost evenly throughout the 4 weeks between each follow-up visit. Conversely, 161 (55%) of the 296 E-z relapses occurred within the 3-day period preceding the patient's appointment (relapse-related hospital visit, RRHV). McNemar's test revealed that the concentration of relapses in this period was statistically significant (P < 0.00011). In addition, 15 out of 26 RRHV without additional therapy showed a spontaneous remission. From a chronological perspective, the common cold and school events as well as up-coming hospital visits may trigger relapses in SDFRNS patients.


Assuntos
Síndrome Nefrótica/fisiopatologia , Síndrome Nefrótica/psicologia , Esteroides , Estresse Fisiológico/complicações , Adolescente , Assistência Ambulatorial , Aniversários e Eventos Especiais , Criança , Pré-Escolar , Resfriado Comum/complicações , Feminino , Humanos , Lactente , Masculino , Síndrome Nefrótica/tratamento farmacológico , Recidiva , Estudos Retrospectivos , Esteroides/uso terapêutico
6.
Am J Med Genet A ; 140(21): 2355-60, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17036344

RESUMO

Renal tubular dysgenesis (RTD) is a developmental abnormality of the renal proximal tubules found in patients with Potter syndrome. We report a female newborn with RTD who has survived for more than 18 months. Infusions of fresh frozen plasma (FFP) in the early neonatal period were effective in raising and maintaining her blood pressure. Peritoneal dialysis was required until the appearance of spontaneous urination at 29 days after birth. Histopathological examinations of the kidney revealed dilated renal tubular lumina and foamy columnar epithelial cells in the renal tubules. Endocrinological studies showed a discrepancy between low plasma renin activity (<0.1 ng/ml/hr) and high active renin concentration (135,000 pg/ml), suggesting an aberration in the renin substrate, angiotensinogen. Direct sequencing analysis revealed two novel mutations in the coding region of the angiotensinogen gene (AGT): a nonsense mutation in exon 2 (c.604C > T) and a frameshift deletion at nucleotide 1290 in exon 5 (c.1290delT). The mutations were in the compound heterozygous state, because each parent had each mutation. These findings suggest that angiotensinogen deficiency is one of the causes of RTD. A treatment of the condition with FFP may help to promote long survival.


Assuntos
Angiotensinogênio/genética , Túbulos Renais Proximais/anormalidades , Mutação , Angiotensinogênio/deficiência , Sequência de Bases , Códon sem Sentido , Análise Mutacional de DNA , Primers do DNA/genética , Feminino , Mutação da Fase de Leitura , Genes Recessivos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Deleção de Sequência
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