小头畸形
张力减退
医学
肌张力过低
神经发育障碍
损失函数
智力残疾
儿科
遗传学
表型
生物
精神科
基因
自闭症
作者
Maria Asif,Arwa Ishaq A. Khayyat,Salem Alawbathani,Uzma Abdullah,Anne Sanner,Theodoros Georgomanolis,Judith Haasters,Kerstin Becker,Birgit Budde,Christian Becker,Holger Thiele,Shahid Mahmood Baig,María Isidoro‐García,Dominic Winter,Hans-Martin Pogoda,Sajjad Muhammad,Matthias Hammerschmidt,Florian Kraft,Ingo Kurth,Helen Martin,Matias Wagner,Peter Nürnberg,Muhammad Sajid Hussain
标识
DOI:10.1016/j.gim.2024.101143
摘要
Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive.We studied five affected individuals from three unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We employed exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing.We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from two unrelated families segregated two homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of two affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process.Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.
科研通智能强力驱动
Strongly Powered by AbleSci AI