Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene
Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene
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DOI：
10.1093/hmg/ddt215
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发表时间：
2013-09-15
影响因子：
3.5
通讯作者：
Griffiths, Lyn R.
中科院分区：
文献类型：
--
作者：
Esposito, Teresa;Lea, Rod A.;Griffiths, Lyn R.
局灶节段性肾小球硬化症（FSGS）是一种疾病过程的结果，攻击肾脏过滤系统，造成严重的疤痕。超过一半的FSGS患者在10年内发展为慢性肾衰竭，最终需要透析或肾移植。目前已知有几种基因可引起遗传性FSGS（ACTN 4、TRPC 6、CD 2AP、INF 2、MYO 1 E和NPHS 2）。这项研究涉及一个大型的，独特的，多代的澳大利亚家系，其中FSGS共分离进行性心脏传导阻滞与明显的X连锁隐性遗传。通过一个经典的连锁和单倍型分析相结合的方法，我们确定了一个21.19 cM的间隔牵连的X染色体。然后，我们使用全外显子组测序方法来鉴定位于该连锁区间内的两个突变基因，NXF 5和ALG 13。两个突变NXF 5-R113 W和ALG 13-T141 L与家系中的疾病表型完全分离，并且在大型健康对照队列中未发现。使用生物信息学工具的分析预测NXF 5基因中的R113 W突变是有害的，并且细胞研究支持在蛋白质的稳定性和定位中的作用，表明该突变在这些共病疾病中的致病作用。现在需要进一步的研究，以确定这些新的突变的功能后果，发展FSGS和心脏传导阻滞在这个谱系，并确定这些突变是否有影响，这些疾病在一般人群中更常见的形式。
Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidneys filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.