The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin.

Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior-Løken syndrome) and ocular motor apraxia (Cogan syndrome). Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion. Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250-amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.

Clinical features and management of arterial hypertension in children with Williams-Beuren syndrome.

BACKGROUND: Hypertension is a common finding in children with Williams-Beuren syndrome (WBS). METHODS: The aim of this retrospective study was to review the clinical presentation of systemic hypertension in WBS children, its origin and management. We included 41 children with confirmed WBS who were referred to the paediatric nephrology or cardiology unit for hypertension. RESULTS: The mean age at diagnosis of hypertension was 4.7 years. Out of 41, 24 patients had systolic blood pressure (BP) between +10 and +30 mmHg above the 95th percentile (1.645 SD), and 20/41 patients had diastolic BP between the 95th percentile (1.645 SD) and >10 mmHg. Thirty-nine patients were asymptomatic. Arteriography, performed in 17/41 patients, revealed a renal artery stenosis (RAS) in 10 patients (58%). Echocardiography was performed in all patients and showed isthmic coarctation in four patients (9%). Calcium channel blockers were used in half of the patients (22/41) and seemed to control hypertension in most cases. Interventional treatment of RAS was performed in five patients (three angioplasty and two surgical bypass). It controlled hypertension in one patient but remained ineffective in the four others. CONCLUSIONS: Medical treatment essentially calcium blockers improved hypertension in most cases. Interventional treatment of RAS has not been encouraging.

Evoluçäo e tratamento da síndrome nefrótica corticossensível da criança / Long-term follow-up and treatment of children with steroid-responsive nephrotic syndrome

Este estudo retrospectivo trata de 88 casos de nefrose corticossensível da criança, acompanhados durante um período de evoluçäo médio de 6,6 ñ6 anos. Dos 78 casos acompanhados durante mais de 2 anos, 14(18 por cento ) näo tiveram recaídas, 64(82 por cento ) tiveram pelo menos uma recaída, sendo que 36(46 por cento ) tornaram-se corticodependentes e 28(36 por cento ) apresentaram recaídas espaçadas. A análise comparativa destes dois últimos grupos mostra uma evoluçäo mais prolongada das formas corticodependentes. A curva de remissäo no grupo tratado somente com corticosteróides comparadas com a observada no grupo que recebeu um tratamento imunossupressor complementar, parece indicar que o beneficío destes agentes é real somente a curto e a médio prazos, apesar dos dois grupos de pacientes näo serem homogêneos. Dos 16 casos corticodependentes tratados com Levamisol, 9 continuaram corticodependentes, 3 tiveram recaídas 3-8 meses após o final da corticoterapia, 2 estäo em remissäo 5 a 24 meses sem tratamento e 2 têm um tempo de evoluçäo insuficiente. No final deste estudo, dos 72 casos ainda em observaçäo, 45(62 por cento ) estäo em remissäo há mais de 2 anos sem tratamento, dos quais 14 nunca apresentaram reacaídas, 19 tiveram recaídas espaçadas e 12 eram corticodependentes. 25 crianças (35 por cento ) estäo em remissäo, das quais 17 estäo ainda em tratamento e 8 sem tratamento há menos de 2 anos. 2 crianças foram a óbito por complicaçöes extra-renais. Este estudo confirma o bom prognóstico das nefroses corticossensíveis da criança, apesar da grande frequência de recaídas e é favorável à utilizaçäo adequada da corticoterapia