The Genetic Basis of Dandy-Walker and Other Mid-Hindbrain Malformations

Dandy-Walker 和其他中后脑畸形的遗传基础

• 批准号: 10319325
• 负责人: William B. Dobyns
• 金额: $ 27.8万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319325
• 关键词: Genetic; Basis; Dandy; Walker; Other

PROJECT SUMMARY Our long-term goal for this project is to advance our understanding of developmental disorders of the brainstem and cerebellum, brain structures derived from the embryonic midbrain and hindbrain, which we refer to collectively as mid-hindbrain malformations (MHM). These disorders affect a minimum of 1 per 6-7000 live births, and likely far more as these numbers do not account for cerebellar abnormalities associated with preterm birth or with autism. Further, cerebellar malformations are known to co-occur with several more common developmental disorders including autism, mental retardation and some types of early life epilepsy. With this renewal, we propose to continue using our large and growing cohort of human subjects with MHM to define the genes, pathways and biological mechanisms underlying these developmental disorders. We will use the most recent genomic technology - massively parallel (NextGen) sequencing of targeted gene panels, whole exome sequencing (WXS) or whole genome sequencing (WGS) - combined with older methods to find the causes of both rare and common MHM. In Aim 1, we will continue to search for genes underlying rare single gene causes of MHM that will demonstrate the most important molecular pathways, including pathways that contribute to more common disorders such as autism. As an example, we have identified the first missense mutation of the AUTS2 gene (previously linked to autism) in a child with MHM. In Aim 2, we will turn to the more challenging but also more important problem of Dandy-Walker malformation, the most common MHM in humans. This specific malformation demonstrates substantial causal heterogeneity and has proven difficult to solve with older technologies, making whole exome and genome sequencing approaches essential. Aims 1-2 need to be supported by ongoing subject recruitment, as studies of comparable disorders such as mental retardation and autism have benefited from large numbers of subjects. In Aim 3, we propose to test the biological function of genes and networks identified in Aims 1-2 using new CRISPR/Cas technology to efficiently generate new mouse models of proven and strong candidate MHM-associated genes. For example, we are now generating the first mouse models of Auts2. We expect that these studies will contribute rapidly to more accurate diagnosis and counseling, and over time will lead to development of specific treatments for a subset of these disorders. We predict that studies of mid-hindbrain development will have broad significance for human developmental disorders generally, providing compelling evidence for a connection between cerebellar development and other classes of developmental disorders.

项目概要 我们这个项目的长期目标是增进我们对发育障碍的理解 脑干和小脑，源自胚胎中脑和后脑的大脑结构，我们称之为 统称为中后脑畸形（MHM）。每 6-7000 名活人中至少有 1 人受到这些疾病的影响 出生率，而且可能更多，因为这些数字没有考虑到与以下疾病相关的小脑异常 早产或患有自闭症。此外，已知小脑畸形与其他几种畸形同时发生。 常见的发育障碍包括自闭症、智力低下和某些类型的早期癫痫。 通过这次更新，我们建议继续使用我们庞大且不断增长的 MHM 人类受试者群体来 定义这些发育障碍背后的基因、途径和生物机制。我们将使用 最新的基因组技术 - 目标基因组的大规模并行 (NextGen) 测序、整体 外显子组测序 (WXS) 或全基因组测序 (WGS) - 结合旧方法来查找 罕见和常见 MHM 的原因。在目标1中，我们将继续寻找稀有单一基因的基因 MHM 的基因原因将展示最重要的分子途径，包括 导致更常见的疾病，例如自闭症。作为一个例子，我们已经确定了第一个错义 MHM 儿童的 AUTS2 基因突变（之前与自闭症有关）。在目标 2 中，我们将转向 Dandy-Walker 畸形更具挑战性，但也是更重要的问题，这是最常见的 MHM 人类。这种特定的畸形表现出显着的因果异质性，并且已被证明很难 解决旧技术的问题，使得全外显子组和基因组测序方法变得至关重要。目标 1-2 需要通过持续的受试者招募来支持，因为对精神等类似疾病的研究 发育迟缓和自闭症已从大量受试者中受益。在目标 3 中，我们建议测试 使用新的 CRISPR/Cas 技术，在目标 1-2 中确定基因和网络的生物学功能 有效地生成经过验证的强候选 MHM 相关基因的新小鼠模型。例如， 我们现在正在生成 Auts2 的第一个小鼠模型。我们期望这些研究将迅速做出贡献 更准确的诊断和咨询，随着时间的推移，将导致针对特定疾病的特定治疗方法的开发 这些疾病的子集。我们预测中后脑发育的研究将具有广泛的意义 对于一般人类发育障碍来说，为两者之间的联系提供了令人信服的证据 小脑发育和其他类型的发育障碍。

项目成果

Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum.

1q44 中缺失和易位断点的定位表明丝氨酸/苏氨酸激酶 AKT3 与出生后小头畸形和胼胝体发育不全有关。

• 发表时间: 2007-08
• 影响因子: 9.8
• 作者: Boland, Elena;Clayton;Woo, Victoria G;McKee, Shane;Manson, Forbes D C;Medne, Livija;Zackai, Elaine;Swanson, Eric A;Fitzpatrick, David;Millen, Kathleen J;Sherr, Elliott H;Dobyns, William B;Black, Graeme C M
• 通讯作者: Black, Graeme C M

Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.

描述 SPTAN1 相关表型：从孤立性癫痫到伴有进行性脑萎缩的脑病。

• 发表时间: 2017-09-01
• 作者: Syrbe, Steffen;Harms, Frederike L;Parrini, Elena;Montomoli, Martino;Mütze, Ulrike;Helbig, Katherine L;Polster, Tilman;Albrecht, Beate;Bernbeck, Ulrich;van Binsbergen, Ellen;Biskup, Saskia;Burglen, Lydie;Denecke, Jonas;Heron, Bénédicte;Heyne
• 通讯作者: Heyne

Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription.

智力障碍患者的 TAF8 纯合突变导致检测不到 TAF8 蛋白，但保留了 RNA 聚合酶 II 转录。

• 发表时间: 2018-06-15
• 影响因子: 3.5
• 作者: El;Curry, Cynthia;Ye, Tao;Garnier, Jean;Kolb;Stierle, Matthieu;Downer, Natalie L;Dixon, Mathew P;Negroni, Luc;Berger, Imre;Thomas, Tim;Voss, Anne K;Dobyns, William;Devys, Didier;Tora, Laszlo
• 通讯作者: Tora, Laszlo

Four new patients with Gomez-Lopez-Hernandez syndrome and proposed diagnostic criteria.

四名新的戈麦斯-洛佩兹-埃尔南德斯综合征患者并提出了诊断标准。

• 发表时间: 2013-02
• 作者: Rush, Eric T;Adam, Margaret P;Clark, Robin D;Curry, Cynthia;Hartmann, Julianne E;Dobyns, William B;Olney, Ann Haskins
• 通讯作者: Olney, Ann Haskins

Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.

脑桥小脑发育不全的临床、神经放射学和遗传学发现。

• 发表时间: 2011-01
• 作者: Namavar, Yasmin;Barth, Peter G;Kasher, Paul R;van Ruissen, Fred;Brockmann, Knut;Bernert, Günther;Writzl, Karin;Ventura, Karen;Cheng, Edith Y;Ferriero, Donna M;Basel;Eggens, Veerle R C;Krägeloh;De Meirleir, Linda
• 通讯作者: De Meirleir, Linda