Abstract：
Macular coloboma (MC) is a rare congenital retinochoroidal defect characterized by lesions of different sizes in the macular region. The pathological mechanism underlying congenital MC is unknown. Novel compound heterozygous variations, c.4301delA (p.Asp1434fs*3) and c.5255C>G (p.Ser1752Ter), in the multiple PDZ domain (MPDZ) proteins were identified via whole-exome analysis on the proband with isolated bilateral macular coloboma in a Chinese family. Segregation analysis revealed that each of the unaffected parents was heterozygous for one of the two variants. The results of the in silico and bioinformatics analysis were aligned with the experimental data. The knockdown of MPDZ in zebrafish caused a decrease in the ellipsoid zone, a destruction of the outer limiting membrane, and the subsequent RPE degeneration. Overall, the loss of MPDZ in zebrafish contributed to retinal development failure. These results indicate that MPDZ plays an essential role in the occurrence and maintenance of the macula, and the novel compound heterozygous variations were responsible for an autosomal recessive macular deficiency in this Chinese family.
摘要：
黄斑缺损（MC）是一种罕见的先天性视网膜脉络膜缺损，其特征是黄斑区不同大小的病变。先天性MC的病理机制尚不清楚。新型复合杂合变异，c.4301delA（p。Asp1434fs*3）和c.5255C>G（第Ser1752Ter),在多个PDZ结构域（MPDZ）中，通过对中国家庭中分离的双侧黄斑缺损的先证者进行全外显子组分析，鉴定了MPDZ蛋白。分离分析显示，未受影响的亲本中的每个都是两种变体之一的杂合。计算机模拟和生物信息学分析的结果与实验数据一致。MPDZ在斑马鱼中的击倒引起椭球区的减少，外部限制膜的破坏，以及随后的RPE退化。总的来说,斑马鱼中MPDZ的缺失导致视网膜发育失败。这些结果表明，MPDZ在黄斑的发生和维持中起着至关重要的作用，新的复合杂合变异是该中国家庭常染色体隐性黄斑缺陷的原因。
