在白化病患者的血细胞RNA样本中可以检测到同义和错义变异的意想不到的后果

IF 3.9 3区 医学 Q2 CELL BIOLOGY Pigment Cell & Melanoma Research Pub Date : 2023-07-09 DOI:10.1101/2023.07.07.23292371
V. Michaud, Angèle Sequeira, Elina Mercier, E. Lasseaux, C. Plaisant, S. Hadj-Rabia, S. Whalen, D. Bonneau, A. Dieux-Coeslier, F. Morice-Picard, Juliette Coursimault, B. Arveiler, S. Javerzat
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引用次数: 0

摘要

2型眼皮肤白化病(OCA2)是白化病的第二常见形式,约占全球OCA的30%。与所有类型的OCA一样,患者表现为头发和皮肤色素沉着不足以及严重的视觉异常。我们关注了一个由29名患者组成的亚组,这些患者的基因诊断悬而未决,因为他们在的外显子10或其周围发现的至少一个变体具有不确定的意义(VUS)。通过小基因分析,我们研究了这些VUS对外显子10跳跃的影响,并表明不仅内含子,而且一些同义变体都会导致外显子跳跃增强。我们进一步发现,外显子10的过度跳过可以直接在具有因果变异的患者及其父母的血液样本上检测到,从而避免了侵入性皮肤活检。此外,我们发现,导致缺乏可检测mRNA的变体也可以从血液样本中鉴定出来,如最常见的OCA2致病性错义变体c.1327G>A/p所示。(Val443Ile)。总之,血细胞RNA分析可以测试任何OCA2-VUS对转录产物的潜在影响。这将有助于阐明尚未解决的OCA2患者,并改善遗传咨询。
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Unsuspected consequences of synonymous and missense variants in can be detected in blood cell RNA samples of patients with albinism
Oculocutaneous albinism type 2 (OCA2) is the second most frequent form of albinism and represents about 30% of OCA worldwide. As with all types of OCA, patients present with hypopigmentation of hair and skin as well as severe visual abnormalities. We focused on a subgroup of 29 patients for whom genetic diagnosis was pending because at least one of their identified variants in or around exon 10 of is of uncertain significance (VUS). By minigene assay, we investigated the effect of these VUS on exon 10 skipping and showed that not only intronic but also some synonymous variants can result in enhanced exon skipping. We further found that excessive skipping of exon 10 could be detected directly on blood samples of patients and of their one parent with the causal variant, avoiding invasive skin biopsies. Moreover, we show that variants which result in lack of detectable mRNA can be identified from blood samples as well, as shown for the most common OCA2 pathogenic missense variant c.1327G>A/p.(Val443Ile). In conclusion, blood cell RNA analysis allows testing the potential effect of any OCA2 VUS on transcription products. This should help to elucidate yet unsolved OCA2 patients and improve genetic counseling.
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来源期刊
Pigment Cell & Melanoma Research
Pigment Cell & Melanoma Research 医学-皮肤病学
CiteScore
8.90
自引率
2.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Pigment Cell & Melanoma Researchpublishes manuscripts on all aspects of pigment cells including development, cell and molecular biology, genetics, diseases of pigment cells including melanoma. Papers that provide insights into the causes and progression of melanoma including the process of metastasis and invasion, proliferation, senescence, apoptosis or gene regulation are especially welcome, as are papers that use the melanocyte system to answer questions of general biological relevance. Papers that are purely descriptive or make only minor advances to our knowledge of pigment cells or melanoma in particular are not suitable for this journal. Keywords Pigment Cell & Melanoma Research, cell biology, melatonin, biochemistry, chemistry, comparative biology, dermatology, developmental biology, genetics, hormones, intracellular signalling, melanoma, molecular biology, ocular and extracutaneous melanin, pharmacology, photobiology, physics, pigmentary disorders
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