Azuma N, Hotta Y, Tanaka H, Yamada M
Department of Ophthalmology, National Children's Hospital, Tokyo, Japan.
Invest Ophthalmol Vis Sci. 1998 Dec;39(13):2524-8.
Aniridia is caused by a mutation of the PAX6 gene. Haploinsufficiency of the gene product is thought to result in the aniridia phenotype, because most mutations thus far detected have been large deletions encompassing the entire gene and nonsense, frameshift, or splice errors that result in premature translational termination on one of the alleles. Only two missense mutations have been detected in aniridia pedigrees, each of which occurs in its paired domain or homeodomain. In this study, four novel missense mutations were found in three aniridia pedigrees.
Polymerase chain reaction-single-strand conformation polymorphism analysis and sequencing of the PAX6 gene were performed using genomic DNA of three aniridia pedigrees and more than 100 healthy control subjects.
Three mutations occurred in the N-terminal subdomain of the paired domain, namely N17S, I29V, and R44Q, the first two of which were detected on the same allele of one patient. The other mutation (Q178H) was in the linking portion of the paired domain and homeodomain.
These missense mutations give rise to haploinsufficiency by another route, because the missense mutations presented here resulted in an aniridia phenotype indistinguishable from that caused by a heterozygous deletion of the entire PAX6 gene.
无虹膜症由PAX6基因突变引起。基因产物的单倍剂量不足被认为导致了无虹膜症表型，因为迄今为止检测到的大多数突变都是涵盖整个基因的大片段缺失以及导致一个等位基因翻译提前终止的无义、移码或剪接错误。在无虹膜症家系中仅检测到两个错义突变，每个突变都发生在其配对结构域或同源结构域中。在本研究中，在三个无虹膜症家系中发现了四个新的错义突变。
使用三个无虹膜症家系和100多名健康对照者的基因组DNA进行PAX6基因的聚合酶链反应-单链构象多态性分析和测序。
三个突变发生在配对结构域的N端亚结构域，即N17S、I29V和R44Q，其中前两个突变在一名患者的同一等位基因上被检测到。另一个突变（Q178H）位于配对结构域和同源结构域的连接部分。
这些错义突变通过另一种途径导致单倍剂量不足，因为此处呈现的错义突变导致的无虹膜症表型与整个PAX6基因杂合缺失所导致的表型无法区分。
