Abstract：
OBJECTIVE: 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.
CONCLUSIONS: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.
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.
CONCLUSIONS: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.
摘要：
目的：FAM177A1的功能及其与人类疾病的关系在很大程度上是未知的。最近的研究表明FAM177A1是一个关键的免疫相关基因。先前的一项案例研究将FAM177A1与四个兄弟姐妹的神经发育障碍联系起来。
方法：我们在FAM177A1中鉴定了来自三个不相关家族的5个个体，具有双等位基因变异。在斑马鱼模型生物和人类细胞系中研究了FAM177A1的生理功能，其功能丧失变体与受影响的队列相似。
结果：这些个体具有由大头畸形定义的特征性表型，全球发育迟缓，智力残疾,癫痫发作,行为异常,低张力,和步态紊乱。我们表明FAM177A1定位于哺乳动物和斑马鱼细胞中的高尔基复合体。来自FAM177A1缺陷的人成纤维细胞和整个斑马鱼幼虫的RNA-seq和代谢组学数据集的交叉显示与凋亡相关的通路失调，炎症,和细胞增殖的负调控。
结论：我们的数据揭示了FAM177A1的新兴功能，并将FAM177A1相关的神经发育障碍定义为新的临床实体。
方法：我们在FAM177A1中鉴定了来自三个不相关家族的5个个体，具有双等位基因变异。在斑马鱼模型生物和人类细胞系中研究了FAM177A1的生理功能，其功能丧失变体与受影响的队列相似。
结果：这些个体具有由大头畸形定义的特征性表型，全球发育迟缓，智力残疾,癫痫发作,行为异常,低张力,和步态紊乱。我们表明FAM177A1定位于哺乳动物和斑马鱼细胞中的高尔基复合体。来自FAM177A1缺陷的人成纤维细胞和整个斑马鱼幼虫的RNA-seq和代谢组学数据集的交叉显示与凋亡相关的通路失调，炎症,和细胞增殖的负调控。
结论：我们的数据揭示了FAM177A1的新兴功能，并将FAM177A1相关的神经发育障碍定义为新的临床实体。
