The Identification Of A New Pathogenic Gene UGDH In Primary Microcephaly

Objective Primary microcephaly(PM)is a neurodevelopmental disorder highly associated with hereditary,whose pathogenic mechanism is reduced proliferation and premature differentiation of neural progenitor cells(NPCs)caused by cell cycle defects.To date,many disease-causing genes are still uncovered.UGDH was recently identified as a pathogenic gene of epileptic encephalopathy(EE),but patient-derived cerebral organoids showed similar clinical and pathological features to human primary microcephaly,including reduced proliferation of NPCs and volume reduction of cerebral organoids.This study will explore the correlation between UGDH and primary microcephaly.Methods Trio whole exome sequencing(WES)and copy number variations(CNV)detection were performed in a patient with PM and EE.We constructed UGDH knockdown HEK-293 cell lines via sh RNA lentiviral vectors and detected cell cycle and proliferation via flow cytometry.We constructed ugdh knockdown zebrafish models and carried out microscopic morphology observations,behavioral assessments and electrophysiological test.Results In our study,we identified UGDH compound heterozygous mutations in one patient with PM and EE.These UGDH mutations were identified as possible pathogenic variants via bioinformatic analysis.Compared with normal control group,UGDH knockdown HEK-293 cell lines showed diminished DNA synthesis,cell cycle arrest at S phase and slowed cell proliferation.Ugdh knockdown larval zebrafishs showed wide eye distance and significant reduction in body length,head length and brain area,but distances moved and maximum accelerations at both spontaneous activity and light-dark stimulation had no statistic differenced between ugdh knockdown and control groups.And no epilepsy-related electrophysiological signals were detected in ugdh knockdown zebrafishs.Conclusion UGDH may be a novel disease-causing gene of PM,decreased function of UGDH gene may lead to microcephaly via cell cycle arrest in NPCs.