Tory Kálmán, Lacoste Tiphanie, Burglen Lydie, Morinière Vincent, Boddaert Nathalie, Macher Marie-Alice, Llanas Brigitte, Nivet Hubert, Bensman Albert, Niaudet Patrick, Antignac Corinne, Salomon Rémi, Saunier Sophie
INSERM, U574, Paris, France.
J Am Soc Nephrol. 2007 May;18(5):1566-75. doi: 10.1681/ASN.2006101164. Epub 2007 Apr 4.
Joubert syndrome (JS) is an autosomal recessive disorder that is described in patients with cerebellar ataxia, mental retardation, hypotonia, and neonatal respiratory dysregulation. Kidney involvement (nephronophthisis or cystic renal dysplasia) is associated with JS in one fourth of known cases. Mutations in three genes--AHI1, NPHP1, and NPHP6--have been identified in patients with JS. However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood. In an attempt to identify such genetic determinants, a cohort of 28 families with nephronophthisis and at least one JS-related neurologic symptom were screened for mutations in AHI1, NPHP1, and NPHP6 genes. NPHP1 and NPHP6 homozygous or compound heterozygous mutations were found in 13 (46%) and six (21%) unrelated patients, respectively. Two of the 13 patients with NPHP1 mutations carried either a heterozygous truncating mutation in NPHP6 or a heterozygous missense mutation in AHI1. Furthermore, five patients with NPHP1 mutations carried the AHI1 variant R830W, which was predicted to be "possibly damaging" and was found with significantly higher frequency than in healthy control subjects and in patients with NPHP1 mutations without neurologic symptoms (five of 26 versus four of 276 and three of 152 alleles; P < 0.001 and P < 0.002, respectively). In contrast to the variable neurologic and milder retinal phenotype of patients with NPHP1 mutations, patients with NPHP6 mutations presented with a more severe neurologic and retinal phenotype. In conclusion, NPHP1 and NPHP6 are major genes of nephronophthisis associated with JS. Epistatic effects that are provided by heterozygous NPHP6 and AHI1 mutations and variants may contribute to the appearance of extrarenal symptoms in patients with NPHP1 mutations.
Joubert综合征（JS）是一种常染色体隐性疾病，见于患有小脑共济失调、智力发育迟缓、肌张力减退和新生儿呼吸调节异常的患者。在已知病例的四分之一中，肾脏受累（肾单位肾痨或囊性肾发育不良）与JS相关。在JS患者中已鉴定出三个基因——AHI1、NPHP1和NPHP6——的突变。然而，由于NPHP1突变通常导致孤立性肾单位肾痨，因此对易导致神经受累的因素了解甚少。为了确定此类遗传决定因素，对28个患有肾单位肾痨且至少有一种与JS相关神经症状的家庭进行队列研究，筛查AHI1、NPHP1和NPHP6基因的突变。分别在13名（46%）和6名（21%）无亲缘关系的患者中发现了NPHP1和NPHP6纯合或复合杂合突变。13名携带NPHP1突变的患者中有2名携带NPHP6杂合截短突变或AHI1杂合错义突变。此外，5名携带NPHP1突变的患者携带AHI1变体R830W，该变体预计为“可能有害”，其出现频率明显高于健康对照受试者以及无神经症状的NPHP1突变患者（26个等位基因中有5个，276个等位基因中有4个，152个等位基因中有3个；P分别<0.001和P<0.002）。与携带NPHP1突变患者的可变神经和较轻视网膜表型不同，携带NPHP6突变的患者表现出更严重的神经和视网膜表型。总之，NPHP1和NPHP6是与JS相关的肾单位肾痨的主要基因。NPHP6和AHI1杂合突变及变体所提供的上位效应可能导致携带NPHP1突变患者出现肾外症状。
