A 5-base insertion in the γC-crystallin gene is associated with autosomal dominant variable zonular pulverulent cataract
A 5-base insertion in the γC-crystallin gene is associated with autosomal dominant variable zonular pulverulent cataract
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DOI：
10.1007/s004390050021
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发表时间：
2000-05-01
期刊：
影响因子：
5.3
通讯作者：
Hejtmancik, JF
中科院分区：
文献类型：
--
作者：
Ren, ZX;Li, AR;Hejtmancik, JF
一个七代家族，30名成员受到高度可变的常染色体显性小带粉状白内障先前已被描述。我们已经将白内障定位到染色体2 q33-q35上的19 cM间隔，包括γ-晶状体蛋白基因簇。D2 S157的最大视杆评分为4.56（θ =0.02），D2572的最大视杆评分为3.66（θ =0.12），D2572的最大视杆评分为3.57（θ =0.052）。对家系中的个体的假γ E-晶状体蛋白启动子区域的测序和等位基因特异性寡核苷酸分析表明，γ E-晶状体蛋白假基因的激活不太可能导致家族中的白内障。此外，在未受影响的对照组中发现了TATA盒的碱基变化，但未发现Sl结合位点的碱基变化，可以排除其为白内障的唯一原因。为了进一步研究该家族中白内障的潜在遗传机制，已经对高表达的γ C-和γ D-晶状体蛋白基因的外显子进行了测序。γ D-晶状体蛋白基因未显示异常，但在每个受影响的家族成员的一个等位基因中发现γ C-晶状体蛋白基因外显子2内的5-bp重复，并且在未受影响的家族成员和未受影响的对照中均不存在。该突变破坏了γ C-晶状体蛋白编码序列的阅读框架，并被预消化以导致合成具有第一个“Greek key”基序的38个氨基酸和随后的52个随机氨基酸的不稳定的γ C-晶状体蛋白。这一发现表明，适当的协会的突变体β γ-晶体蛋白的寡聚体是不必要的，导致白内障，并可能给我们新的见解白内障形成的遗传机制。
A seven-generation family with 30 members affected by highly variable autosomal dominant zonular pulverulent cataracts has been previously described. We have localized the cataracts to a 19-cM interval on chromosome 2q33-q35 including the gamma-crystallin gene cluster. Maximum rod scores are 4.56 (theta=0.02) with D2S157, 3.66 (theta=0.12) with D2572, and 3.57 (theta=0.052) with CRYG. Sequencing and allele-specific oligonucleotide analysis of the pseudo gamma E-crystallin promoter region from individuals in the pedigree suggest that activation of the gamma E-crystallin pseudo gene is unlikely to cause the cataracts in the family. In addition, base changes in the TATA box but not the Spl-binding site have been found in unaffected controls and can be excluded as a sole cause of cataracts. In order to investigate the underlying genetic mechanism of cataracts in this family further, exons of the highly expressed gamma C- and gamma D-crystallin genes have been sequenced. The gamma D-crystallin gene shows no abnormalities, but a 5-bp duplication within exon 2 of the gamma C-crystallin gene has been found in one allele of each affected family member and is absent from both unaffected family members and unaffected controls. This mutation disrupts the reading frame of the gamma C-crystallin coding sequence and is pre-dieted to result in the synthesis of an unstable gamma C-crystallin with 38 amino acids of the first "Greek key" motif followed by 52 random amino acids. This finding suggests that the appropriate association of mutant beta gamma-crystallins into oligomers is not necessary to cause cataracts and may give us new insights into the genetic mechanism of cataract formation.