SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.
SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization.
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DOI：
10.1093/hmg/ddaa166
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发表时间：
2020-11-04
影响因子：
3.5
通讯作者：
Thomas MG
中科院分区：
文献类型：
--
作者：
Kuht HJ;Han J;Maconachie GDE;Park SE;Lee ST;McLean R;Sheth V;Hisaund M;Dawar B;Sylvius N;Mahmood U;Proudlock FA;Gottlob I;Lim HT;Thomas MG
中央凹发育不全，视神经讨论缺陷和前段发育不良是由SLC38A8突变引起的常染色体隐性遗传病。SLC38A8是一种推测的谷氨酰胺转运蛋白，在视网膜的感光层中有很强的表达。由于缺乏视网膜发育和眼球震颤特征的定量数据，以往的研究受到限制。在这项多中心研究中，使用定制靶向下一代测序（NGS）基因面板从511名眼球震颤患者中鉴定SLC38A8突变。我们报道了16个新的SLC38A8突变。第六跨膜结构域最常被错义SLC38A8突变破坏。90%的病例在NGS之前被误诊为pax6相关表型或眼部白化病。我们利用高分辨率光学相干断层扫描技术对SLC38A8突变患者的体内视网膜发育进行了表征。所有患者都有严重程度的视网膜发育阻滞，缺乏中央凹，没有锥体光感受器外段延长。中央凹特化特征的丧失，如外节段延长，意味着中央凹锥体密度降低，这有助于降低视力。与其他疾病（如白化病或PAX6突变）不同，SLC38A8突变会在早期阶段阻止视网膜发育，导致视网膜发育不全和严重的表型。
Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development with lack of a foveal pit and no cone photoreceptor outer segment lengthening. Loss of foveal specialization features such as outer segment lengthening implies reduced foveal cone density, which contributes to reduced visual acuity. Unlike other disorders (such as albinism or PAX6 mutations) which exhibit a spectrum of foveal hypoplasia, SLC38A8 mutations have arrest of retinal development at an earlier stage resulting in a more under-developed retina and severe phenotype.
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影响因子：
3.7
作者：
Margolis DJ;Gartland AJ;Singer JH;Detwiler PB
通讯作者：
Detwiler PB
影响因子：
9.9
作者：
Papageorgiou E;Pilat A;Proudlock F;Lee H;Purohit R;Sheth V;Vasudevan P;Gottlob I
通讯作者：
Gottlob I
产前人类视网膜视网膜层的发育。
影响因子：
4.2
作者：
Hendrickson A
通讯作者：
Hendrickson A
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
4.5
作者：
Ramtohul, Prithvi;Comet, Alban;Denis, Daniele
通讯作者：
Denis, Daniele