MAP1B变异破坏神经元迁移:来自三个新家族的见解。

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Jessica Archer, Matt Edwards, Thomas Macdougall, Anne Baxter, Himanshu Goel
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引用次数: 0

摘要

MAP1B(微管相关蛋白1B)编码对神经元迁移、轴突引导和皮层回路形成至关重要的细胞骨架调节因子。MAP1B致病变异(DCVs)最近被认为是以智力残疾、癫痫和皮质畸形为特征的神经发育障碍的原因,包括脑室周围结节性异位(PVNH)和多小回畸形(PMG)。然而,与map1b相关疾病相关的表型和神经影像学谱仍然不完全确定。我们描述了来自3个不相关家族的7名患病个体,他们携带致病性MAP1B变异。临床、神经影像学和遗传数据在新兴文献的背景下进行分析,以描述与MAP1B功能障碍相关的致病机制和表型变异。所有个体都携带功能缺失的MAP1B变体。临床特征包括全面发育迟缓、智力残疾、行为失调和局灶性癫痫。神经影像学显示,5例有神经影像学的病例中,有4例的PVNH在前部占优。这些发现强化了MAP1B在细胞骨架调节、神经元定位和突触连接中的核心作用。来自动物和细胞模型的功能数据支持微管稳定性受损、生长锥动力学改变和轴突分支失调的机制。我们的病例系列扩展了与map1b相关疾病相关的临床和放射学表型,并强调了它在人类皮质生成中作为关键细胞骨架调节因子的地位。系统的基因型-表型相关性和功能研究需要为诊断解释提供信息,并探索map1b相关疾病的治疗途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MAP1B Variants Disrupt Neuronal Migration: Insights From Three Novel Families.

MAP1B (microtubule-associated protein 1B) encodes a cytoskeletal regulator critical for neuronal migration, axon guidance, and cortical circuit formation. Disease-causing variants (DCVs) in MAP1B have recently emerged as a cause of neurodevelopmental disorders characterized by intellectual disability, epilepsy, and cortical malformations, including periventricular nodular heterotopia (PVNH) and polymicrogyria (PMG). However, the phenotypic and neuroimaging spectrum associated with MAP1B-related disease remains incompletely defined. We describe seven affected individuals from three unrelated families with pathogenic MAP1B variants. Clinical, neuroimaging, and genetic data were analyzed in the context of emerging literature to delineate the pathogenic mechanisms and phenotypic variability associated with MAP1B dysfunction. All individuals carried loss of function MAP1B variants. Clinical features included global developmental delay, intellectual disability, behavioural dysregulation, and focal epilepsy. Neuroimaging revealed anteriorly predominant PVNH in four of five cases with neuroimaging available. These findings reinforce MAP1B's central role in cytoskeletal regulation, neuronal positioning, and synaptic connectivity. Functional data from animal and cell models support a mechanism involving impaired microtubule stabilization, altered growth cone dynamics, and dysregulated axon branching. Our case series expands the clinical and radiological phenotype associated with MAP1B-related disorders and highlights its position as a key cytoskeletal regulator in human corticogenesis. Systematic genotype-phenotype correlation and functional studies are needed to inform diagnostic interpretation and explore therapeutic avenues in MAP1B-associated disease.

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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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