Unraveling the Role of WDR91: Case Report of a Previously Unrecognized Clinical Entity.

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Nikolaos M Marinakis, Afrodite Kampouraki, Danai Veltra, Faidon-Nikolaos Tilemis, Maria Vasilopoulou, Aikaterini Dokou, Elissavet Georgiadou, Euthalia Karavergou, Maria Christolouka, Alexis Alexopoulos, Dimitra Kirillidi, Maria Goudesidou, Konstantina Kosma, Christalena Sofocleous, Periklis Makrythanasis
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引用次数: 0

Abstract

WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.

揭示WDR91的作用:一个以前未被认识的临床实体的病例报告。
WDR91是一种含有WD40重复结构域的蛋白,是内体运输、溶酶体功能和自噬的关键调节因子。它作为Rab7效应物,与WDR81形成复合物,调节磷脂酰肌醇3-激酶(PI3K)活性、内体成熟和溶酶体稳态。WDR91的功能丧失变异被认为与内体积聚、货物降解受损和神经变性有关。在本报告中,提出了一种常染色体隐性神经发育障碍,与近亲家族的WDR91功能丧失有关。患者表现为严重的小头畸形、畸形特征和器官肿大,并伴有早发性精神运动迟缓、张力低下、感音神经性听力障碍和视力障碍。全外显子组测序(WES)鉴定出一个纯合子剪接位点变异NM_014149.4:c。1395+1G>A,预计会破坏供体部位,并被归类为可能致病(PVS1, PM2)。人口数据库和我们的内部队列中都没有这种变异。功能分析支持该变异的致病作用。正如WDR91敲除模型所证明的那样,WDR91缺乏会导致神经元丢失、皮层变薄和大脑发育受损。我们的研究扩大了wdr91相关疾病的临床和遗传谱,并强调了进一步研究阐明wdr91相关发病机制的精确分子机制的必要性。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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