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Abstract：
Though many mutations have been identified to be associated with the occurrence of congenital cataract, pathogenic loci in some affected families are still unknown. Clinical data and genomic DNA were collected from a four-generation Chinese family. Candidate mutations were independently verified for cosegregation in the whole pedigree. Linkage analysis showed that the disease-causing mutation was located between 1p36.21 and 1p36.33. Analysis of the whole-exome sequencing data combined with linkage analysis identified a novel pathogenic variant (g.2451906C>T) at intron 4 of Pantothenate kinase 4 (PANK4 protein, PANK4 gene) in 1p36.32|606162. This variant showed complete cosegregation with the phenotype in the pedigree. The mutation was not detected in 106 normal controls nor in 40 sporadic congenital cataract patients. The mutation was demonstrated to significantly reduce the expression of the PANK4 protein level in the blood of cataract patients than that in normal individuals by ELISA. Pank4-/- mice showed a cataract phenotype with increased numbers of apoptotic lens epithelial cells, fiber cell aggregation, and significant mRNA variation of crystallin family members. Thus, the association of a new entity of an autosomal dominant cataract with mutations in PANK4, which influences cell proliferation, apoptosis of lens epithelial cells, crystallin abnormalities, and fiber cell derangement, subsequently induces cataract.
摘要：
尽管许多突变已被确定与先天性白内障的发生有关，一些受影响家庭的致病位点仍然未知。从一个四代中国家庭收集临床数据和基因组DNA。独立验证了候选突变在整个家系中的共分离。连锁分析表明，致病突变位于1p36.21和1p36.33之间。全外显子组测序数据分析与连锁分析相结合，在泛酸激酶4的内含子4（PANK4蛋白，PANK4基因)在1p36.32|606162。该变体显示与谱系中的表型完全共分离。在106名正常对照和40名散发性先天性白内障患者中均未检测到该突变。通过ELISA证明，该突变可显著降低白内障患者血液中PANK4蛋白的表达水平。Pank4-/-小鼠显示白内障表型，凋亡晶状体上皮细胞数量增加，纤维细胞聚集，和晶状体蛋白家族成员的显著mRNA变异。因此，常染色体显性遗传白内障的新实体与PANK4突变的关联，影响细胞增殖，晶状体上皮细胞凋亡，晶状体蛋白异常，和纤维细胞紊乱，随后诱发白内障。
