RESUMEN
This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin beta2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction.
Asunto(s)
Marcadores Genéticos/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Glomérulos Renales/fisiopatología , Podocitos , Actinina/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas del Citoesqueleto/genética , Genoma , Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Laminina/genética , Proteínas de la Membrana/genética , Mutación , Fosfoinositido Fosfolipasa C/genética , Proteinuria/genética , Canales Catiónicos TRPC/genética , Canal Catiónico TRPC6 , Proteínas WT1/genéticaRESUMEN
Focal segmental glomerulosclerosis (FSGS) is a histologic diagnosis in several kidney diseases characterized by proteinuria and a severe decrease in kidney function. Mutations in several genes were found in patients with primary FSGS, one of which is a CD2-associated protein CD2AP (originally referred to as CMS). This gene encodes an adaptor protein that plays a role in endocytosis, cell motility, and cell survival. Mice deficient in Cd2ap (the mouse homolog) die due to kidney failure, while heterozygous mice develop lesions similar to those of FSGS patients. In the kidney, CD2AP regulates the actin cytoskeleton. The only previously described patient with CD2AP mutation had a severely truncated protein. In this study, we describe a patient with a novel mutation resulting in a premature stop codon yielding a protein truncated by only 4%. This shortened CD2AP protein displays a significantly decreased F-actin binding efficiency in vitro with no expression of the mutated allele in the patient's lymphocytes. Heterozygous expression of the CD2AP mutation in both parents did not lead to any kidney pathology, as both have normal glomerular filtration rates and no proteinuria.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas del Citoesqueleto/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Homocigoto , Mutación , Actinas/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Biopsia , Cadáver , Preescolar , Codón de Terminación/genética , Consanguinidad , Tasa de Filtración Glomerular , Glomeruloesclerosis Focal y Segmentaria/cirugía , Humanos , Glomérulos Renales/metabolismo , Glomérulos Renales/fisiología , Glomérulos Renales/ultraestructura , Trasplante de Riñón , Masculino , Datos de Secuencia Molecular , Técnicas de Amplificación de Ácido Nucleico , Unión Proteica , Estructura Terciaria de Proteína , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Resultado del TratamientoRESUMEN
In a 17-year-old woman with absent sexual development and a congenital nephrotic syndrome leading to renal failure, the Denys-Drash syndrome was diagnosed after development of an ovarian dysgerminoma. The Denys-Drash syndrome is characterised by the triad: progressive nephropathy due to diffuse mesangial sclerosis, male pseudo-hermaphroditism (XY karyotype with ambiguous or female genital organs) and an increased risk of developing Wilms' tumour and gonadoblastoma. The syndrome is generally caused by a genetic defect in the Wilms' tumour suppressor 1 gene (WT1 gene). A WT1 mutation and XY karyotype were also found in this patient. The WT1 gene encodes a transcription factor playing an important role in renal and genital development. The diagnosis of Denys-Drash syndrome had important consequences for the follow-up and treatment of the patient. The second gonad and the native kidneys were removed due to the increased risk of malignancy. Moreover, the finding of a XY karyotype could result in serious psychic problems. Physicians responsible for the health of adults are confronted more and more often with the consequences of childhood diseases. This case illustrates the necessity to inform such physicians about previously untreatable genetic diseases of childhood so that the adequate medical management of these patients can be guaranteed.
Asunto(s)
Síndrome de Denys-Drash/genética , Trastornos del Desarrollo Sexual/genética , Genes del Tumor de Wilms , Neoplasias Ováricas/genética , Anomalías Urogenitales/genética , Adolescente , Síndrome de Denys-Drash/psicología , Femenino , Disgenesia Gonadal/genética , Humanos , Mutación , Calidad de VidaRESUMEN
BACKGROUND: The heterogeneity of mitochondrial cytopathies is characteristic for this group of disorders, which preferentially affect the muscle and nerve system. The A3243G transition in the tRNA(Leu(UUR)) gene has been associated with slowly progressive forms of focal segmental glomerulosclerosis (FSGS). Here we present a patient who developed a severe nephrotic syndrome during her first pregnancy, which persisted after delivery, and proved resistant to immunosuppressive therapy. A sister of our patient had developed diabetes mellitus. We analysed the DNA for the presence of the mitochondrial DNA (mtDNA) A3243G transition. METHODS: DNA was isolated from peripheral blood leukocytes and urine sediments. Polymerase chain reaction was performed to amplify the mtDNA. Restriction enzyme analysis was used to detect the presence of the A3243G transition. Quantitative analysis of the A3243G mutation was done using the pyrosequencing technique. RESULTS: Quantitative analysis revealed a proportion of mutated mtDNA of 30% in the leukocytes and 68% in the urine sediments of the proband. On further analysis, we also found the transition in the mother, the diabetic sister and the daughter of the proband. CONCLUSION: MtDNA abnormalities can cause a steroid-resistant nephrotic syndrome, histologically characterized by FSGS. Physicians should be especially mindful of mitochondrial abnormalities when hearing loss, diabetes mellitus or neuromuscular disorders are present in the patient or family members.
Asunto(s)
ADN Mitocondrial/genética , Síndrome Nefrótico/genética , ARN de Transferencia de Leucina/genética , Adulto , Secuencia de Bases , ADN/sangre , ADN/aislamiento & purificación , Cartilla de ADN , Femenino , Humanos , Riñón/patología , Masculino , Mutación Missense , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Familial forms of steroid-resistant nephrotic syndrome with the histologic findings of focal-segmental glomerulosclerosis have frequently a genetic basis. For the non-familial forms this is still unresolved. PATIENTS AND METHODS: Ten children with non-familial steroid-resistant nephrotic syndrome along with focal-segmental glomerulosclerosis were tested for mutations in the WT-1 and NPHS2 genes. RESULTS: In 1 patient, a mutation in intron 9 of the WT-1 gene and in 1 patient a heterozygous NPHS2 mutation could be detected. Both abnormalities are important for the treatment modalities and prognosis. CONCLUSION: Additional studies will have to provide a solid basis for the recommendation of mutation analysis in non-familial steroid-resistant focal-segmental glomerulosclerosis.
