Richter Leslie, Flodman Pamela, Barria von-Bischhoffshausen Fernando, Burch Douglas, Brown Sandra, Nguyen Linda, Turner Julia, Spence M Anne, Bateman J Bronwyn
Department of Ophthalmology, Rocky Mountain Lions Eye Institute, Aurora, Colorado 80045, USA.
Am J Med Genet A. 2008 Apr 1;146A(7):833-42. doi: 10.1002/ajmg.a.32236.
We studied 28 individuals from a four-generation Chilean family (ADC54) including 13 affected individuals with cataracts, microcornea and/or corneal opacity. All individuals underwent a complete ophthalmologic exam. We screened with a panel of polymorphic DNA markers for known loci that cause autosomal dominant cataracts, if mutated, and refined the locus using the ABI Prism Linkage Mapping Set Version 2.5, and calculated two-point lod scores. Novel PCR primers were designed for the three coding exons, including intron-exon borders, of the candidate gene alpha A crystallin (CRYAA). Clinically, affected individuals had diverse and novel cataracts with variable morphology (anterior polar, cortical, embryonal, fan-shaped, anterior subcapsular). Microcornea and corneal opacity was evident in some. Marker D21S171 gave a lod score of 4.89 (theta(m) = theta(f) = 0). CRYAA had a G414A transition that segregated with the disease and resulted in an amino acid alteration (R116H). The phenotypic variability within this family was significant with novel features of the cataracts and a corneal opacity. With the exception of iris coloboma, the clinical features in all six previously reported families with mutations in the CRYAA gene were found in this family. We identified a novel G414A transition in exon 3 of CRYAA that co-segregated with an autosomal dominant phenotype. The resulting amino acid change R116H is in a highly conserved region and represents a change in charge. The genotype-phenotype correlation of this previously unreported mutation provides evidence that other factors, genetic and/or environmental, may influence the development of cataract as a result of this alteration.
我们研究了一个四代智利家族（ADC54）中的28名个体，其中包括13名患有白内障、小角膜和/或角膜混浊的患者。所有个体均接受了全面的眼科检查。我们使用一组多态性DNA标记物对已知可导致常染色体显性白内障（若发生突变）的基因座进行筛查，并使用ABI Prism连锁图谱集版本2.5对该基因座进行精细定位，同时计算两点连锁分析的对数优势分数。针对候选基因αA晶状体蛋白（CRYAA）的三个编码外显子（包括内含子 - 外显子边界）设计了新的PCR引物。临床上，患病个体患有形态各异的新型白内障（前极性、皮质性、胚胎性、扇形、前囊下性）。部分个体存在小角膜和角膜混浊。标记物D21S171的对数优势分数为4.89（θ(m)=θ(f)=0）。CRYAA基因发生了G414A转换，该转换与疾病共分离并导致氨基酸改变（R116H）。这个家族中的表型变异性显著，白内障和角膜混浊具有新特征。除虹膜缺损外，该家族具有先前报道的所有六个CRYAA基因突变家族的临床特征。我们在CRYAA基因的外显子3中鉴定出一个新的G414A转换，它与常染色体显性表型共分离。由此产生的氨基酸变化R116H位于一个高度保守的区域，并且代表了电荷的改变。这种先前未报道的突变的基因型 - 表型相关性提供了证据，表明其他遗传和/或环境因素可能会因这种改变而影响白内障的发展。
