Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa
Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa
复制标题
DOI：
10.1186/s13023-019-1275-2
复制
发表时间：
2019-12-19
影响因子：
3.7
通讯作者：
Tsang, Stephen H.
中科院分区：
文献类型：
--
作者：
Oh, Jin Kyun;Lima de Carvalho, Jose Ronaldo, Jr.;Tsang, Stephen H.
背景：Kelch样蛋白7(KLHL7)的突变代表了遗传性视网膜营养不良的一种最近被描述且迄今特征不佳的病因。KLHL7基因的显性突变是导致孤立的非综合征性视网膜色素变性(RP)的原因之一。相比之下，已知的隐性功能丧失突变会导致Crisponi或Bohring-Opitz样的冷诱导出汗综合征-3(BOS-3)。本研究对5例KLHL7介导的常染色体显性遗传性遗传性早幼粒细胞白血病(ADRP)的表型和进展进行了研究。对这些患者的临床评估包括全面的眼科检查、全场视网膜电图(FfERG)和成像，包括眼底照相、光谱域光学相干断层扫描(SD-OCT)、短波眼底自发荧光(SW-AF)和近红外眼底自发荧光(NIR-AF)。分子诊断采用全外显子组测序或基因面板测试。对三名患者的病情进展进行了监测，平均随访时间为4.5+/-2.9年。除了文献中记录的导致Crisponi或Bohring-Opitz样冷汗综合征的隐性功能丧失等位基因外，对本研究中发现的所有变异进行了蛋白质建模。结果：3名患者的基因检测在背部结构域的3-盒基序中发现了两个新的变异：c.472T>；C：p(Cys158Arg)和c.433A>；T：p(Asn145Tyr)。临床影像显示3例患者同时在短波房颤和近红外房颤上形成高自体荧光环，除1例外，其余均可见弥漫性外周和乳头周围萎缩。SD-OCT显示了一种表型谱，从外视网膜中央凹旁萎缩伴中央凹保留到广泛的视网膜变薄和光感受器丧失。黄斑囊样水肿的发生率很高，五名患者中有四名受到影响。显性等位基因与隐性功能丧失等位基因的蛋白质模型显示，显性等位基因定位于BTB和背侧结构域，而隐性等位基因则定位于Kelch结构域。结论：我们报道了5例KLHL7介导的adrp患者的表型，两种新的编码变异体，以及使用SW-AF和NIR-AF的成像生物标记物。这些发现可能会影响未来基于基因的ADRP治疗，并为阐明KLHL7介导的RP发病机制的机制研究铺平道路。
Background: Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 +/- 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome.Results: Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain.Conclusions: We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.