Manes Gaël, Mamouni Sonia, Hérald Emilie, Richard Anne-Claire, Sénéchal Audrey, Aouad Karim, Bocquet Béatrice, Meunier Isabelle, Hamel Christian P
Institut National de la Santé et de la Recherche Médicale, U1051, Institute for Neurosciences of Montpellier, Montpellier, France.
University of Montpellier, Montpellier, France.
Mol Vis. 2017 Apr 3;23:198-209. eCollection 2017.
Sixteen different mutations in the guanylate cyclase activator 1A gene (), have been previously identified to cause autosomal dominant cone dystrophy (adCOD), cone-rod dystrophy (adCORD), macular dystrophy (adMD), and in an isolated patient, retinitis pigmentosa (RP). The purpose of this study is to report on two novel mutations and the patients' clinical features.
Clinical investigations included visual acuity and visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, and full-field and multifocal electroretinogram (ERG) recordings. was screened by Sanger sequencing in a cohort of 12 French families with adCOD, adCORD, and adMD.
We found two novel mutations-one amino acid deletion, c.302_304delTAG (p.Val101del), and one missense mutation, c.444T>A (p.Asp148Glu)-each of which was found in one family. The p.Asp148Glu mutation affected one of the Ca-binding amino acids of the EF4 hand, while the p.Val101del mutation resulted in the in-frame deletion of Valine-101, localized between two Ca-binding aspartic acid residues at positions 100 and 102 of the EF3 hand. Both families complained of visual acuity loss worsening with age. However, the p.Asp148Glu mutation was present in one family with adCOD involving abnormal cone function and an absence of macular atrophy, whereas p.Val101del mutation was encountered in another family with adMD without a generalized cone defect.
The two novel mutations described in this study are associated with distinct phenotypes, MD for p.Val101del and COD for p.Asp148Glu, with no intrafamilial phenotypic heterogeneity.
先前已鉴定出鸟苷酸环化酶激活剂1A基因（）中的16种不同突变可导致常染色体显性遗传性视锥细胞营养不良（adCOD）、视锥-视杆细胞营养不良（adCORD）、黄斑营养不良（adMD），并且在一名孤立患者中导致色素性视网膜炎（RP）。本研究的目的是报告两种新的突变以及患者的临床特征。
临床检查包括视力和视野测试、眼底检查、高分辨率光谱域光学相干断层扫描（OCT）、眼底自发荧光成像以及全视野和多焦视网膜电图（ERG）记录。在一个由12个患有adCOD、adCORD和adMD的法国家庭组成的队列中，通过桑格测序对进行筛查。
我们发现了两种新的突变——一种氨基酸缺失，c.302_304delTAG（p.Val101del），以及一种错义突变，c.444T>A（p.Asp148Glu）——每个突变分别在一个家庭中发现。p.Asp148Glu突变影响了EF4结构域中一个与钙结合的氨基酸，而p.Val101del突变导致缬氨酸-101的框内缺失，该缺失位于EF3结构域中第100和102位两个与钙结合的天冬氨酸残基之间。两个家庭均主诉视力随着年龄增长而下降。然而，p.Asp148Glu突变存在于一个患有adCOD的家庭中，该家庭存在视锥细胞功能异常且无黄斑萎缩，而p.Val101del突变出现在另一个患有adMD的家庭中，该家庭无全身性视锥细胞缺陷。
本研究中描述的两种新突变与不同的表型相关，p.Val101del突变导致MD，p.Asp148Glu突变导致COD，且家系内无表型异质性。
