Laboratory of the Biology and Pathology of the Eye, Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, and General University Hospital in Prague, Prague, Czech Republic2Department of Ophthalmology, First Faculty of Medicine, Charles University in Prague, and General University Hospital in Prague, Prague, Czech Republic.
JAMA Ophthalmol. 2013 Oct;131(10):1296-303. doi: 10.1001/jamaophthalmol.2013.405.
Posterior polymorphous corneal dystrophy (PPCD) is a very rare disorder characterized by primary changes of the posterior corneal layers. Sequence variants in 3 genes are associated with the development of PPCD, including ZEB1 that is responsible for PPCD3. Evidence suggests at least 1 more gene remains to be identified.
To determine the molecular genetic cause of PPCD3.
We performed extensive ophthalmological examination, including rotating Scheimpflug imaging technology and specular microscopy, and direct sequencing of the ZEB1 coding region. Comprehensive review of published PPCD3-causing variants was undertaken.
Ophthalmology department of a university hospital.
Four Czech probands.
Results of ophthalmological examination and direct sequencing of the ZEB1 coding region.
The following 2 novel frameshift mutations within ZEB1 were identified: c.2617dup in exon 8 in a 22-year-old woman, considered to be most likely de novo in origin, and c.698dup in exon 6 in a 20-year-old man. The first patient had mild changes consistent with PPCD and bilateral best-corrected visual acuity of 1.00. The corneal phenotype of the patient in the second case was more severe, with best-corrected visual acuity of 0.40 OD and 0.05 OS. Corneas of both probands were abnormally steep (keratometry readings, flat ≥ 47.4 diopters [D] and steep ≥ 49.2 D) with increased pachymetry values but no pattern indicative of keratoconus. Specular microscopy in both patients revealed reduced endothelial cell density (range, 1055/mm² to 1655/mm²). Both probands had a history of surgery for inguinal hernia; the male patient also reported hydrocele.
Nucleotide changes within the coding region of ZEB1 underlie the pathogenesis of PPCD in 4 of 23 Czech probands (17%). The cumulative de novo ZEB1 mutation rate is at least 14%. Possible involvement of ZEB1 sequence variants not readily identified by direct sequencing of coding regions needs to be further investigated. Our findings also have implications for patient counseling.
后多形性角膜营养不良（PPCD）是一种非常罕见的疾病，其特征为角膜后层的原发性改变。3 个基因的序列变异与 PPCD 的发生有关，包括负责 PPCD3 的 ZEB1。有证据表明，至少还有 1 个基因有待发现。
确定 PPCD3 的分子遗传原因。
我们进行了广泛的眼科检查，包括旋转 Scheimpflug 成像技术和共焦显微镜检查，以及 ZEB1 编码区的直接测序。对已发表的 PPCD3 致病变异进行了全面回顾。
大学医院的眼科。
4 名捷克先证者。
眼科检查和 ZEB1 编码区直接测序的结果。
发现 ZEB1 中以下 2 个新的移码突变：22 岁女性的外显子 8 中的 c.2617dup，推测最有可能是从头发生的，20 岁男性的外显子 6 中的 c.698dup。第一个患者有轻度改变，符合 PPCD，双眼最佳矫正视力为 1.00。第二个病例的角膜表型更严重，右眼最佳矫正视力为 0.40，左眼为 0.05。两名先证者的角膜均异常陡峭（角膜曲率读数，平坦≥47.4 屈光度[D]和陡峭≥49.2 D），角膜厚度增加，但无圆锥角膜的典型模式。两名患者的共焦显微镜检查均显示内皮细胞密度降低（范围为 1055/mm²至 1655/mm²）。两名先证者均有腹股沟疝手术史；男性患者还报告有鞘膜积液。
ZEB1 编码区的核苷酸变化是 23 名捷克先证者中 4 名（17%）PPCD 的发病机制。从头发生的 ZEB1 突变率至少为 14%。需要进一步研究直接测序编码区不易识别的 ZEB1 序列变异的可能参与情况。我们的发现还对患者咨询具有重要意义。
