编码线粒体异柠檬酸脱氢酶γ亚基的IDH3G作为x连锁视网膜色素变性的新候选基因的鉴定。

IF 6.6 1区医学 Q1 GENETICS & HEREDITY

Genetics in Medicine Pub Date : 2025-03-19 DOI:10.1016/j.gim.2025.101418

Lorenzo Bianco , Julien Navarro , Christelle Michiels , Riccardo Sangermano , Christel Condroyer , Aline Antonio , Alessio Antropoli , Camille Andrieu , Emily M. Place , Eric A. Pierce , Said El Shamieh , Vasily Smirnov , Vasiliki Kalatzis , Luke Mansard , Anne-Françoise Roux , Béatrice Bocquet , José-Alain Sahel , Isabelle Meunier , Kinga M. Bujakowska , Isabelle Audo , Christina Zeitz

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引用次数: 0

摘要

目的：色素性视网膜炎（RP）是一种遗传异质性的视网膜退行性疾病，其特征是杆状和锥状光感受器的丧失，导致视力障碍和失明。迄今为止，x连锁RP与三个基因（RPGR, RP2, OFD1）的变异有关，而三个位点（RP6, RP24, RP34）的遗传缺陷尚未确定。本研究的目的是确定一个新的候选基因的x连锁RP。方法：参与者从受RP影响的遗传未解决的男性个体中确定，他们在三个转诊中心进行了基因组测序、外显子组测序或通过直接Sanger测序进行候选基因筛选。具体而言，在国家罕见视网膜疾病参考中心（REFERET，法国巴黎）鉴定了两个先证，在马萨诸塞州眼耳医院（Boston， MA， USA）鉴定了两个先证，在国家遗传性感觉疾病参考中心（MAOLYA，法国蒙伯利埃）鉴定了一个先证。利用生物信息学预测、蛋白质表达分析和线粒体功能分析评估鉴定变异的致病性。结果：我们在5个无亲缘关系的非综合征性RP患者中发现了IDH3G （HGNC:5386）中4个罕见的单核苷酸变异（位于X染色体RP34位点）以及一个完全的基因缺失。在所有可用的家族成员中，变异与表型分离。在所有病例中，疾病严重程度为中等。没有人高度近视。IDH3G编码线粒体异柠檬酸脱氢酶（IDH3）的γ亚基，这是一种参与柠檬酸循环的酶，在光感受器的内段表达。IDH3A和IDH3B的变异，编码IDH3的其他亚基，已经与非综合征性常染色体隐性RP相关。生物信息学预测和功能分析支持本研究中发现的变异的致病作用，可能是由于酶活性和线粒体功能的部分丧失。结论：我们的研究结果表明，IDH3G的变异是x连锁RP的一个新原因，可能是通过损害线粒体功能并最终导致光感受器变性。

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Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa

Purpose

Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (RPGR, RP2, and OFD1), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP.

Methods

Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays.

Results

We identified 4 rare single-nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly through partial loss of enzymatic activity and mitochondrial function.

Conclusion

Our findings suggest that variants in IDH3G are a novel cause of X-linked RP.

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来源期刊

Genetics in Medicine 医学-遗传学

CiteScore

15.20

自引率

6.80%

发文量

857

审稿时长

1.3 weeks

期刊介绍： Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health. GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.