Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
Kidney Int. 2011 Dec;80(11):1239-45. doi: 10.1038/ki.2011.284. Epub 2011 Aug 24.
Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in the first three decades of life. Mutations in 13 genes (NPHP1-NPHP11, AHI1, and CC2D2A) cause NPHP with ubiquitous expression of the corresponding proteins consistent with the multiorgan involvement of NPHP-related diseases. The genotype-phenotype correlation in these ciliopathies can be explained by gene locus heterogeneity, allelism, and the impact of modifier genes. In some NPHP-related ciliopathies, the nature of the recessive mutations determines disease severity. In order to define the genotype-phenotype correlation more clearly, we evaluated a worldwide cohort of 440 patients from 365 families with NPHP-related ciliopathies, in whom both disease-causing alleles were identified. The phenotypes were ranked in the order of severity from degenerative to degenerative/dysplastic to dysplastic. A genotype of two null alleles caused a range of phenotypes, with an increasing order of severity of NPHP1, NPHP3, NPHP4, NPHP5, NPHP2, NPHP10, NPHP6, to AHI1. Only NPHP6 showed allelic influences on the phenotypes; the presence of two null mutations caused dysplastic phenotypes, whereas at least one missense allele rescued it to a milder degenerative phenotype. We also found nine novel mutations in the NPHP genes. Thus, our studies have important implications for genetic counseling and planning of renal replacement therapy.
肾单位肾痨病(NPHP),一种常染色体隐性遗传的囊性肾病,是导致生命最初三十年终末期肾衰竭的最常见遗传原因。13 个基因(NPHP1-NPHP11、AHI1 和 CC2D2A)的突变导致 NPHP,相应蛋白广泛表达,与 NPHP 相关疾病的多器官受累一致。这些纤毛病变中的基因型-表型相关性可以用基因座异质性、等位基因、以及修饰基因的影响来解释。在一些 NPHP 相关纤毛病变中,隐性突变的性质决定了疾病的严重程度。为了更清楚地定义基因型-表型相关性,我们评估了来自 365 个 NPHP 相关纤毛病变家系的 440 名患者的全球队列,其中确定了两个致病等位基因。表型按从退行性到退行性/发育不良到发育不良的严重程度排序。两个无效等位基因的基因型导致一系列表型,严重程度从 NPHP1、NPHP3、NPHP4、NPHP5、NPHP2、NPHP10、NPHP6 逐渐增加,直到 AHI1。只有 NPHP6 的表型存在等位基因影响;两个无效突变的存在导致发育不良表型,而至少一个错义等位基因将其挽救为更温和的退行性表型。我们还在 NPHP 基因中发现了九个新突变。因此,我们的研究对遗传咨询和肾脏替代治疗计划具有重要意义。