Parisi M A, Doherty D, Eckert M L, Shaw D W W, Ozyurek H, Aysun S, Giray O, Al Swaid A, Al Shahwan S, Dohayan N, Bakhsh E, Indridason O S, Dobyns W B, Bennett C L, Chance P F, Glass I A
Department of Pediatrics, Children's Hospital and Regional Medical Center and the University of Washington School of Medicine, Seattle, WA 98195, USA.
J Med Genet. 2006 Apr;43(4):334-9. doi: 10.1136/jmg.2005.036608. Epub 2005 Sep 9.
Joubert syndrome (JS) is an autosomal recessive disorder characterised by hypotonia, ataxia, mental retardation, altered respiratory pattern, abnormal eye movements, and a brain malformation known as the molar tooth sign (MTS) on cranial MRI. Four genetic loci have been mapped, with two genes identified (AHI1 and NPHP1).
We screened a cohort of 117 JS subjects for AHI1 mutations by a combination of haplotype analysis and sequencing of the gene, and for the homozygous NPHP1 deletion by sequencing and marker analysis.
We identified a total of 15 novel AHI1 mutations in 13 families, including nonsense, missense, splice site, and insertion mutations, with some clustering in the WD40 domains. Eight families were consanguineous, but no single founder mutation was apparent. In addition to the MTS, retinal dystrophy was present in 11 of 12 informative families; however, no subjects exhibited variable features of JS such as polydactyly, encephalocele, colobomas, or liver fibrosis. In contrast to previous reports, we identified two families with affected siblings who developed renal disease consistent with nephronophthisis (NPH) in their 20s. In addition, two individuals with classic NPH were found to have homozygous NPHP1 deletions.
Overall, 11% of subjects had AHI1 mutations, while approximately 2% had the NPHP1 deletion, representing a total of less than 15% in a large JS cohort. Some preliminary genotype-phenotype correlations are possible, notably the association of renal impairment, specifically NPH, in those with NPHP1 deletions. Subjects with AHI1 mutations may be at risk of developing both retinal dystrophy and progressive kidney disease.
Joubert综合征（JS）是一种常染色体隐性疾病，其特征为肌张力减退、共济失调、智力发育迟缓、呼吸模式改变、眼球运动异常以及头颅磁共振成像（MRI）上显示的一种称为磨牙症候（MTS）的脑畸形。已确定了四个基因座，鉴定出两个基因（AHI1和NPHP1）。
我们通过单倍型分析和基因测序相结合的方法，对117名JS患者进行了AHI1突变筛查，并通过测序和标记分析对纯合NPHP1缺失进行了检测。
我们在13个家系中总共鉴定出15个新的AHI1突变，包括无义突变、错义突变、剪接位点突变和插入突变，其中一些聚集在WD40结构域。八个家系为近亲结婚，但未发现明显的单一奠基者突变。除了MTS外，12个信息充分的家系中有11个存在视网膜营养不良；然而，没有患者表现出JS的可变特征，如多指畸形、脑膨出、缺损或肝纤维化。与先前的报道不同，我们发现两个家系中受影响的兄弟姐妹在20多岁时出现了与肾单位肾痨（NPH）一致的肾脏疾病。此外，发现两名典型NPH患者存在纯合NPHP1缺失。
总体而言，11%的患者有AHI1突变，约2%的患者有NPHP1缺失，在一个大型JS队列中总计不到15%。一些初步的基因型-表型相关性是可能的，特别是在那些有NPHP1缺失的患者中，肾脏损害，特别是NPH的关联。有AHI1突变的患者可能有发生视网膜营养不良和进行性肾病的风险。
