Autosomal Dominant Retinitis Pigmentosa-Associated TOPORS Protein Truncating Variants Are Exclusively Located in the Region of Amino Acid Residues 807 to 867.
Autosomal Dominant Retinitis Pigmentosa-Associated TOPORS Protein Truncating Variants Are Exclusively Located in the Region of Amino Acid Residues 807 to 867.
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DOI：
10.1167/iovs.63.5.19
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发表时间：
2022-05-02
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
TOPORS基因杂合性截断变异可导致常染色体显性遗传性视网膜色素变性(ADRP)。本研究的目的是调查是否所有的杂合截断变异体，包括拷贝数变异体(CNV)，都是致病的。通过内部数据集和现有数据库收集和审查TOPORS截断变体。有截断变异的个体接受了眼科评估。在7个家系中检测到6个截断变异体。在3个无RP的家系中检测到3个N端截断变异体，在4个典型的RP家系中检测到另外3个突变体。基于内部数据集和已发表的文献，在47个RP家系中鉴定出17个截断变体。除1个外，所有的RP相关截短等位基因都分布在TOPORS的最后一个外显子上，并聚集在氨基酸残基807~867位(46/47，97.9%)。相反，在gnomAD数据库中，只有1个截断等位基因(1/27，3.7%)在该区域，其余的截断等位基因在该区域外(26/27，96.3%)，表明致病截断变异显著聚集在第80 7~86 7位残基上(χ2=65.6，P=1.1×10-17)。此外，在对照人群中记录了三个涉及TOPORS N末端的CNV，但在受影响的患者中没有记录到。本研究表明，TOPORS的所有致病截断变异体都聚集在807~867位残基上，而位于该区域外的截断变异体和涉及N末端的CNV与RP无关。一种显性负效应，而不是单倍性不足，被推测是潜在的发病机制。这些发现为解释TOPORS和其他基因在类似情况下的变异提供了有价值的信息，特别是对于CNV。
Heterozygous truncating variants of TOPORS have been reported to cause autosomal dominant retinitis pigmentosa (adRP). The purpose of this study was to investigate whether all heterozygous truncating variants, including copy number variants (CNVs), are pathogenic. TOPORS truncating variants were collected and reviewed through an in-house dataset and existing databases. Individuals with truncating variants underwent ophthalmological evaluation. Six truncating variants were detected in seven families. Three N-terminus truncating variants were detected in three families without RP, and the other three were identified in four unrelated families with typical RP. Based on the in-house dataset and published literature, 17 truncating variants were identified in 47 families with RP. All RP-associated truncating alleles, except one, were distributed in the last exon of TOPORS and clustered in amino acid residues 807 to 867 (46/47, 97.9%). Conversely, in the gnomAD database, only one truncating allele (1/27, 3.7%) was in this region, and the others were outside (26/27, 96.3%), suggesting that the pathogenic truncating variants were significantly clustered in residues 807 to 867 (χ2 = 65.6, P = 1.1 × 10–17). Additionally, three CNVs involving the N-terminus of TOPORS were recorded in control populations but were absent in affected patients. This study suggests that all pathogenic truncating variants of TOPORS were clustered in residues 807 to 867, whereas the truncating variants outside this region and the CNVs involving the N-terminus were not associated with RP. A dominant-negative effect, rather than haploinsufficiency, is speculated to be the underlying pathogenesis. These findings provide valuable information for interpreting variation in TOPORS and other genes in similar situations, especially for CNVs.
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