Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY
Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-03-25 DOI:10.1007/s00439-024-02655-4
Charlotte Herbst, Viktoria Bothe, Meret Wegler, Susanne Axer-Schaefer, Séverine Audebert-Bellanger, Jozef Gecz, Benjamin Cogne, Hagit Baris Feldman, Anselm H C Horn, Anna C E Hurst, Melissa A Kelly, Michael C Kruer, Alina Kurolap, Annie Laquerriere, Megan Li, Paul R Mark, Markus Morawski, Mathilde Nizon, Tomi Pastinen, Tilman Polster, Pascale Saugier-Veber, Jang SeSong, Heinrich Sticht, Jens T Stieler, Isabelle Thifffault, Clare L van Eyk, Pascale Marcorelles, Myriam Vezain-Mouchard, Rami Abou Jamra, Henry Oppermann
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引用次数: 0

Abstract

Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.

Abstract Image

DOCK4 的杂合子功能缺失变体会导致神经发育迟缓和小头畸形。
神经元是神经系统的基本解剖结构和功能结构,神经元分化或神经元形成的缺陷与各种精神和神经发育障碍有关。细胞骨架的动态变化对这一过程至关重要,而细胞骨架的变化主要由细胞分裂专用因子 4(DOCK4)通过激活 RAC1 控制。在此,我们临床描述了 7 名患者(6 男 1 女)的 DOCK4 变异和轻度至重度全面发育迟缓的重叠表型。其他症状包括协调或步态异常、小头畸形、非特异性脑畸形、肌张力低下和癫痫发作。四人携带错义变体(其中三人从头检测到),三人携带空变体(其中两人是母体遗传)。杂合子错义变体的分子建模表明,其中大多数变体会影响 DOCK4 的球状结构。在转染的神经-2A细胞中进行的体外功能表达研究表明,所有错义变体都会影响神经元的生长。此外,Dock4基因敲除的神经-2A细胞在促进神经元生长方面也表现出缺陷。我们的研究结果(包括临床、分子和功能数据)表明,DOCK4的功能缺失变体可能会导致不同程度的伴有小头畸形的新型神经发育障碍。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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