Genetic insights into Tietz albinism-deafness syndrome: A new dominant-negative mutation in MITF

IF 3.9 3区 医学 Q2 CELL BIOLOGY Pigment Cell & Melanoma Research Pub Date : 2024-03-04 DOI:10.1111/pcmr.13166
Kohei Yamamoto, Ken Okamura, Kazumasa Wakamatsu, Shosuke Ito, Kozue Akabane, Yosuke Arai, Junnosuke Kawaguchi, Yutaka Hozumi, Tamio Suzuki
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Abstract

Tietz albinism-deafness syndrome (TADS) is a rare and severe manifestation of Waardenburg syndrome that is primarily linked to mutations in MITF. In this report, we present a case of TADS resulting from a novel c.637G>C mutation in MITF (p.Glu213Gln; GenBank Accession number: NM_000248). A 3-year-old girl presented with congenital generalized hypopigmentation of the hair, skin, and irides along with complete sensorineural hearing loss. Histopathological and electron microscopy investigations indicated that this variant did not alter the number of melanocytes in the skin but significantly impaired melanosome maturation within melanocytes. Comprehensive melanin analysis revealed marked reductions in both eumelanin (EM) and pheomelanin (PM) rather than changes in the EM-to-PM ratio observed in oculocutaneous albinism. We conducted an electrophoretic mobility shift assay to investigate the binding capability of the identified variant to DNA sequences containing the E-box motif along with other known variants (p.Arg217del and p.Glu213Asp). Remarkably, all three variants exhibited dominant-negative effects, thus providing novel insights into the pathogenesis of TADS. This study sheds light on the genetic mechanisms underlying TADS and offers a deeper understanding of this rare condition and its associated mutations in MITF.

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蒂茨白化病-耳聋综合征的遗传学研究:MITF 的一种新显性阴性突变。
蒂茨白化病-失聪综合征(TADS)是瓦登堡综合征的一种罕见而严重的表现,主要与 MITF 的突变有关。在本报告中,我们介绍了一例因 MITF 的新型 c.637G>C 突变(p.Glu213Gln;GenBank 编号:NM_000248)而导致的 TADS 病例。一名 3 岁女孩出现先天性全身毛发、皮肤和虹膜色素沉着,并伴有完全性感音神经性听力损失。组织病理学和电子显微镜检查表明,这种变异并没有改变皮肤中黑色素细胞的数量,但却严重影响了黑色素细胞内黑色素小体的成熟。综合黑色素分析表明,黑素(EM)和黑褐素(PM)均明显减少,而不是眼部白化病中观察到的EM-PM比例变化。我们进行了电泳迁移试验,研究已鉴定变体与含有 E-box motif 的 DNA 序列以及其他已知变体(p.Arg217del 和 p.Glu213Asp)的结合能力。值得注意的是,这三个变异体都表现出显性负效应,从而为 TADS 的发病机制提供了新的见解。这项研究揭示了 TADS 的遗传机制,加深了人们对这种罕见疾病及其相关 MITF 突变的理解。
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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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