Compound heterozygous KCNV2 variants contribute to cone dystrophy with supernormal rod responses in a Chinese family.
Compound heterozygous KCNV2 variants contribute to cone dystrophy with supernormal rod responses in a Chinese family.
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DOI：
10.1002/mgg3.1795
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发表时间：
2021-10
影响因子：
2
通讯作者：
Ma Y
中科院分区：
文献类型：
--
作者：
Liu M;Zhu Y;Huang L;Jiang W;Wu N;Song Y;Lu Y;Ma Y
视锥细胞营养不良伴超常视杆细胞反应（CDSRR）是一种常染色体隐性遗传性视网膜疾病，其特征为近视、色觉障碍、夜盲、视物恐怖和眼球震颤。CDSRR是由KCNV 2突变引起的，KCNV 2是编码名为Kv8.2的电沉默Kv亚基（Kvs）的基因。招募一个中国CDSRR家系。进行了完整的眼科临床检查，以澄清表型。使用全外显子组测序（WES）进行遗传学检查。此外，通过桑格测序验证候选基因。进行了体外表达分析，包括免疫印迹、定量真实的时间PCR（qRT-PCR）和免疫共沉淀实验，以研究鉴定的基因变体的致病机制。WES从先证者中鉴定出两个KCNV 2杂合突变。桑格测序证实了患者的父母分别携带这两种突变。进一步的体外功能实验表明，突变的等位基因分别导致Kv8.2蛋白不能表达和不能与Kv2.1蛋白相互作用。这项研究扩大了KCNV 2突变谱。也可以推断，CDSRR具有广泛的异质性。基于先前的研究和本研究，进一步证实了Kv8.2蛋白不能表达以及Kv8.2蛋白不能与Kv2.1相互作用可能是CDSRR的病因。一名男性CDSRR患者的KCNV 2基因存在复合杂合变异（c.731G>C和c.280dup）。功能分析证实，c.280dup可能导致非感知mRNA衰减（NMD），从而使蛋白质无法表达。此外，还批准了c.731G>C突变，其中Kv2.1蛋白不能与Kv8.2蛋白相互作用。对于CDSRR的病因，我们的研究表明，Kv8.2蛋白沿着表达的缺失以及Kv2.1蛋白和Kv8.2蛋白之间相互作用的失败可能是导致CDSRR的原因。
Cone dystrophy with supernormal rod response (CDSRR) is an autosomal recessive retinal disorder characterized by myopia, dyschromatopsia, nyctalopia, photophobia, and nystagmus. CDSRR is caused by mutations in KCNV2, the gene encoding for an electrically silent Kv subunit (Kvs) named Kv8.2. A Chinese CDSRR family was recruited. Complete ophthalmology clinical examinations were performed to clarify the phenotype. Genetic examination was underwent using whole exome sequencing (WES). In addition, a candidate gene was validated by Sanger sequencing. Expression analysis in vitro including immunoblotting, quantitative real‐time PCR (qRT‐PCR), and co‐immunoprecipitation experiments was performed to investigate the pathogenic mechanism of the identified gene variants. WES identified two KCNV2 heterozygous mutations from the proband. Sanger sequencing validated that the patient's parents had, respectively, carried those two mutations. Further in vitro functional experiments indicated that the mutated alleles had led the Kv8.2 proteins to fail in expressing and interacting with the Kv2.1 protein, respectively. This study expanded the KCNV2 mutation spectrum. It can also be deduced that CDSRR has a broad heterogeneity. It is further confirmed that the inability expression of Kv8.2 proteins and the failure of Kv8.2 proteins to interact with Kv2.1 may have accounted for the etiology of CDSRR based on previous studies and this study. Compound heterozygous variations (c.731G>C and c.280dup) were revealed in the KCNV2 gene of a male with CDSRR. Functional analysis had confirmed that c.280dup may led to non‐sensed mRNA decay (NMD), which in turn makes the protein unable to express. In addition, it is also approved that the c.731G>C mutation, in which the Kv2.1 protein failed to interact with Kv8.2 proteins. For the etiology of CDSRR, our study suggested that the inability expression of Kv8.2 proteins along with the failure of interactions between the Kv2.1 protein and the Kv8.2 proteins may account for the occurrence of the CDSRR.
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Stargardt病：临床特征，分子遗传学，动物模型和治疗选择。
DOI：
10.1136/bjophthalmol-2016-308823
发表时间：
2017-01
期刊：
The British journal of ophthalmology
影响因子：
--
作者：
Tanna P;Strauss RW;Fujinami K;Michaelides M
通讯作者：
Michaelides M
影响因子：
4.2
作者：
Georgiou M;Robson AG;Fujinami K;Leo SM;Vincent A;Nasser F;Cabral De Guimarães TA;Khateb S;Pontikos N;Fujinami-Yokokawa Y;Liu X;Tsunoda K;Hayashi T;Vargas ME;Thiadens AAHJ;de Carvalho ER;Nguyen XT;Arno G;Mahroo OA;Martin-Merida MI;Jimenez-Rolando B;Gordo G;Carreño E;Ayuso C;Sharon D;Kohl S;Huckfeldt RM;Wissinger B;Boon CJF;Banin E;Pennesi ME;Khan AO;Webster AR;Zrenner E;Héon E;Michaelides M
通讯作者：
Michaelides M
影响因子：
1.6
作者：
Grigg, John R.;Holder, Graham E.;Jamieson, Robyn V.
通讯作者：
Jamieson, Robyn V.
影响因子：
4.1
作者：
Michaelides, M;Holder, GE;Moore, AT
通讯作者：
Moore, AT
影响因子：
13.7
作者：
Zelinger, Lina;Wissinger, Bernd;Banin, Eyal
通讯作者：
Banin, Eyal