Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.
Gene. 2024 Oct 20;925:148600. doi: 10.1016/j.gene.2024.148600. Epub 2024 May 23.
Traboulsi syndrome is an under-recognized syndromic form of ectopia lentis (EL) caused by the aspartate beta-Hydroxylase (ASPH) variant. The genotype-phenotype profile of ASPH-associated disease is poorly understood due to the rarity of the condition.
We conducted targeted next-generation sequencing and bioinformatics analysis to identify potentially pathogenic ASPH variants in the cohort. Furthermore, we characterized the expression pattern of ASPH and major components of the zonules using single-cell RNA-sequencing (scRNA-seq) and evaluated the genotype-phenotype correlations by combining our data and those from the literature.
We identified a novel missense variant c.2075G > A (p.G692D) and a recurrent nonsense variant c.1126C > G (p.R376*) of ASPH in two pedigrees from a Chinese cohort of EL. Both probands were 5-year-old boys with canonical facial dysmorphisms and bilateral anteriorly-dislocated lenses. Other ocular comorbidities included microspherophakia, shallow anterior chamber, and narrow chamber angel. No cardiac involvements or filtering blebs were identified. The single-cell expression atlas of ciliary epithelium demonstrated the coexpression of ASPH with FBN1, FBN2, and LTBP2 in the non-pigmented ciliary epithelium cells. Furthermore, molecular modeling simulation of p.G692D revealed increased affinity to the cb EGF-like domain and a subsequent destabilized calcium-binding motif. The genotype-phenotype analysis demonstrated that patients with cardiac involvements all harbored biallelic truncation variants.
The data from this study provide new insights into the genotype-phenotype profile of ASPH-associated disease and implicate the potential role of ASPH in the pathogenesis of EL.
Traboulsi 综合征是一种由天门冬氨酸 β-羟化酶（ASPH）变异引起的未被充分认识的晶状体异位（EL）综合征。由于该疾病的罕见性，ASPH 相关疾病的基因型-表型特征了解甚少。
我们通过靶向下一代测序和生物信息学分析，在该队列中鉴定出潜在的致病性 ASPH 变体。此外，我们使用单细胞 RNA 测序（scRNA-seq）来描述 ASPH 及其主要的悬韧带成分的表达模式，并通过结合我们的数据和文献中的数据来评估基因型-表型相关性。
我们在一个来自中国 EL 患者的队列中，发现了两个家系中 ASPH 的一个新的错义变异 c.2075G>A（p.G692D）和一个反复出现的无义变异 c.1126C>G（p.R376*）。两名先证者均为 5 岁男孩，具有典型的面部畸形和双侧晶状体前脱位。其他眼部合并症包括小眼球、浅前房和窄房角。未发现心脏受累或滤过泡。睫状上皮的单细胞表达图谱显示，ASPH 与 FBN1、FBN2 和 LTBP2 在非色素睫状上皮细胞中共同表达。此外，p.G692D 的分子建模模拟显示与 cb EGF 样结构域的亲和力增加，随后钙结合基序不稳定。基因型-表型分析表明，有心脏受累的患者均携带双等位基因截断变异。
本研究的数据为 ASPH 相关疾病的基因型-表型特征提供了新的见解，并提示 ASPH 可能在 EL 的发病机制中起作用。
