Kolkova Zuzana, Durdik Peter, Holubekova Veronika, Durdikova Anna, Jesenak Milos, Banovcin Peter
Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
Front Pediatr. 2024 Jan 25;12:1339664. doi: 10.3389/fped.2024.1339664. eCollection 2024.
The mutations in the (retinitis pigmentosa GTPase regulator) gene are the most common cause of X-linked retinitis pigmentosa (XLRP), a rare genetic disorder affecting the photoreceptor cells in the retina. Several reported cases identified this gene as a genetic link between retinitis pigmentosa (RP) and primary ciliary dyskinesia (PCD), characterised by impaired ciliary function predominantly in the respiratory tract. Since different mutations in the same gene can result in various clinical manifestations, it is important to describe a correlation between the gene variant and the observed phenotype.
Two young brothers from a non-consanguineous Slovak family with diagnosed retinal dystrophy and recurrent respiratory infections were examined. Suspected PCD was diagnosed based on a PICADAR questionnaire, nasal nitric oxide analysis, transmission electron microscopy, high-speed video microscopy analysis, and genetic testing.
We identified a novel frameshift mutation NM_001034853: c.309_310insA, p.Glu104Argfs*12, resulting in a complex X-linked phenotype combining PCD and RP. In our patients, this mutation was associated with normal ultrastructure of respiratory cilia, reduced ciliary epithelium, more aciliary respiratory epithelium, shorter cilia, and uncoordinated beating with a frequency at a lower limit of normal beating, explaining the clinical manifestation of PCD in our patients.
The identified novel pathogenic mutation in the gene expands the spectrum of genetic variants associated with the X-linked PCD phenotype overlapping with RP, highlighting the diversity of mutations contributing to the disorder. The described genotype-phenotype correlation can be useful in clinical practice to recognise a broader spectrum of PCD phenotypes as well as for future research focused on the genetic basis of PCD, gene interactions, the pathways implicated in PCD pathogenesis, and the role of RPGR protein for the proper functioning of cilia in various tissues throughout the body.
视网膜色素变性GTP酶调节蛋白（RPGR）基因突变是X连锁视网膜色素变性（XLRP）最常见的病因，XLRP是一种罕见的遗传性疾病，会影响视网膜中的光感受器细胞。几例已报道的病例将该基因确定为视网膜色素变性（RP）和原发性纤毛运动障碍（PCD）之间的遗传联系，PCD的特征主要是呼吸道纤毛功能受损。由于同一基因的不同突变可导致多种临床表现，因此描述基因变异与观察到的表型之间的相关性很重要。
对来自斯洛伐克一个非近亲家庭的两名患有视网膜营养不良和反复呼吸道感染的年轻兄弟进行了检查。基于PICADAR问卷、鼻一氧化氮分析、透射电子显微镜检查、高速视频显微镜分析和基因检测，诊断出疑似PCD。
我们鉴定出一种新的移码突变NM_001034853：c.309_310insA，p.Glu104Argfs*12，导致一种结合了PCD和RP的复杂X连锁表型。在我们的患者中，这种突变与呼吸道纤毛的正常超微结构、纤毛上皮减少、更多无纤毛的呼吸道上皮、较短的纤毛以及频率在正常跳动下限的不协调跳动相关，这解释了我们患者中PCD的临床表现。
在RPGR基因中鉴定出的新的致病突变扩展了与X连锁PCD表型重叠且与RP相关的基因变异谱，突出了导致该疾病的突变的多样性。所描述的基因型-表型相关性在临床实践中可能有助于识别更广泛的PCD表型，以及用于未来聚焦于PCD遗传基础、基因相互作用、PCD发病机制中涉及的途径以及RPGR蛋白对全身各种组织中纤毛正常功能的作用的研究。
