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.
摘要：
Tietz白化病-耳聋综合征（TADS）是Waardenburg综合征的一种罕见且严重的表现，主要与MITF中的突变有关。在这份报告中,我们介绍了一例由MITF中的新型c.637G>C突变引起的TADS（p。Glu213Gln；GenBank登录号：NM_000248）。一名3岁女孩表现为头发的先天性全身性色素减退，皮肤,以及完全的感觉神经性听力损失。组织病理学和电子显微镜研究表明，该变体并未改变皮肤中黑素细胞的数量，但显着损害了黑素细胞内的黑素体成熟。综合黑色素分析显示，在眼皮肤白化病中观察到的真黑素（EM）和phoomelanin（PM）均显着降低，而不是EM与PM比率的变化。我们进行了电泳迁移率变化测定，以研究鉴定的变体与包含E-box基序的DNA序列以及其他已知变体的结合能力（p。Arg217del和p.Glu213Asp）。值得注意的是,所有三个变体都表现出显性负面影响，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，并对MITF中的这种罕见疾病及其相关突变有了更深入的了解。
