FAM177A1 是一种定位于高尔基体复合物的蛋白，其功能丧失可导致一种新型神经发育障碍。
Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.
机构信息
Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA; Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA.
Department of Obstetrics and Gynecology, MedStar Washington Hospital Center and Georgetown University Hospital, Washington, DC.
出版信息
Genet Med. 2024 Sep;26(9):101166. doi: 10.1016/j.gim.2024.101166. Epub 2024 May 17.
PURPOSE
The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings.
METHODS
We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort.
RESULTS
These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation.
CONCLUSION
Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.
目的
FAM177A1 的功能及其与人类疾病的关系在很大程度上尚不清楚。最近的研究表明 FAM177A1 是一个关键的免疫相关基因。以前的一项病例研究将 FAM177A1 与 4 名兄弟姐妹的神经发育障碍联系起来。
方法
我们在 3 个无关联的家庭中发现了 5 名个体，他们在 FAM177A1 中存在双等位基因变异。我们使用类似于受影响队列的功能丧失变异体在斑马鱼模型生物和人类细胞系中研究 FAM177A1 的生理功能。
结果
这些个体具有共同的表型特征，包括大头畸形、全面发育迟缓、智力残疾、癫痫发作、行为异常、低张力和步态障碍。我们表明 FAM177A1 在哺乳动物和斑马鱼细胞中定位于高尔基体复合物。FAM177A1 缺陷型人成纤维细胞的 RNA 测序和代谢组学数据集以及整个斑马鱼幼虫的交集表明，与细胞凋亡、炎症和细胞增殖负调控相关的途径发生失调。
结论
我们的数据阐明了 FAM177A1 的新兴功能，并将 FAM177A1 相关的神经发育障碍定义为一种新的临床实体。
Zotero 插件