15 例 ADNP 综合征病例的纵向基因型-表型(文兰省问卷调查)特征突显了变异蛋白质长度和结构特征与男性交流能力的相关性。

IF 2.8 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Neuroscience Pub Date : 2024-01-29 DOI:10.1007/s12031-024-02189-4
Jospeh Levine, Alexandra Lobyntseva, Shula Shazman, Fahed Hakim, Illana Gozes
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引用次数: 0

摘要

活动依赖性神经保护蛋白(ADNP)对神经发育至关重要,ADNP的新生突变会导致ADNP综合征。从大脑病理学的角度来看,tauopathy 在年轻时就已被证实,这意味着发育迟缓与早期/加速的神经退行性变相结合。考虑到潜在的基因型-表型差异和年龄依赖性,我们在此对 15 名患者(1-27 岁)进行了群组评估,采用了 1-3 次家长(看护人)纵向访谈(维尼兰 3 问卷),历时数年。我们的研究结果表明,这些儿童发育迟缓,甚至发育停滞,但在幼年时期可能会有突飞猛进的发展。严重后果与截短的高影响突变(换句话说,剩余的突变蛋白长度)以及受测者的年龄相关,证实了发育迟缓与加速衰老的假设。突变蛋白长度与沟通能力之间存在明显的相关性,这意味着 ADNP 对沟通能力的影响很大。此外,研究还发现,ADNP 的两个先前描述的表观遗传特征之间存在相关性,这两个特征都强调运动行为的异常获得,而核定位信号周围的截短突变则是受影响的主要因素。最后,所有患者的年龄似乎都相当于 1-6 岁,需要进行疾病调整治疗,例如 ADNP 衍生的候选药物 NAP(达武内肽),该药物最近在患有神经退行性疾病、进行性核上性麻痹(PSP)(一种晚发 tauopathy)的女性患者中显示出疗效。
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Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males

Activity-dependent neuroprotective protein (ADNP) is essential for neurodevelopment and de novo mutations in ADNP cause the ADNP syndrome. From brain pathologies point of view, tauopathy has been demonstrated at a young age, implying stunted development coupled with early/accelerated neurodegeneration. Given potential genotype–phenotype differences and age-dependency, we have assessed here a cohort of 15 individuals (1–27-year-old), using 1–3 longitudinal parent (caretaker) interview/s (Vineland 3 questionnaire) over several years. Our results indicated developmental delays, or even developmental arrests, coupled with potential spurts of development at early ages. Severe outcomes correlated with the truncating high impact mutation, in other words, the remaining mutated protein length as well as with the tested individual age, corroborating the hypothesis of developmental delays coupled with accelerated aging. A significant correlation was noted between mutated protein length and communication, implying a high impact of ADNP on communicative skills. Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1–6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy.

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来源期刊
Journal of Molecular Neuroscience
Journal of Molecular Neuroscience 医学-神经科学
CiteScore
6.60
自引率
3.20%
发文量
142
审稿时长
1 months
期刊介绍: The Journal of Molecular Neuroscience is committed to the rapid publication of original findings that increase our understanding of the molecular structure, function, and development of the nervous system. The criteria for acceptance of manuscripts will be scientific excellence, originality, and relevance to the field of molecular neuroscience. Manuscripts with clinical relevance are especially encouraged since the journal seeks to provide a means for accelerating the progression of basic research findings toward clinical utilization. All experiments described in the Journal of Molecular Neuroscience that involve the use of animal or human subjects must have been approved by the appropriate institutional review committee and conform to accepted ethical standards.
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