RESUMO
BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS. METHODS: We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease. We carried out a whole genome sequencing in two affected and two healthy family members. The function of found podocin variant was studied using co-immunoprecipitation and immunohistochemistry. Podocyte gene sequences were analyzed in a cohort of Finnish non-familial SRNS patients. RESULTS: A heterozygous de novo deletion, c.988_989delCT in NPHS2, was found in all affected family members and in none of their healthy relatives, non-familial patients or controls. No other SRNS-related gene variant, coding or non-coding co-segregated with the disease phenotype in the family. While the truncated podocin remained able to bind nephrin, the expression of nephrin was fragmented and podocin expression reduced. The gene analysis of the non-familial SRNS patients revealed few variants. CONCLUSION: The role of podocin variants in nephrotic syndrome may be more varied than previously thought.
Assuntos
Resistência a Medicamentos/genética , Genes Dominantes , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Síndrome Nefrótica/genética , Deleção de Sequência , Esteroides/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Finlândia , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hereditariedade , Heterozigoto , Humanos , Lactente , Recém-Nascido , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Transplante de Rim , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/terapia , Linhagem , Fenótipo , Diálise Renal , Fatores de Tempo , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
Congenital ciliary dysfunctions are recessively inherited disorders. The disorder is poorly recognized, if the patient has no situs inversus. The diagnosis is delayed, being made on the average at the age of over five years. The review deals with a recent European multinational survey of the occurrence, genetics, diagnostics and treatment of congenital ciliary dysfunctions. Data of Finnish pediatric patients under treatment have also been collected for the survey. The number of congenital ciliary dysfunctions found in Finland is approximately one fifth of that found in other Nordic countries.
