Sodium channel expression and transcript variation in the developing brain of human, Rhesus monkey, and mouse

Neurobiology of Disease

Snezana Maljevic¹  Victoria Perreau²  Anjali Garg³  Lauren Eldershaw³  Géza Berecki³  Christopher A. Reid³  Steven Petrou³  Jacqueline Heighway³  Alicia Sedo³ 

[1]Praxis Precision Medicines, Inc., Cambridge, MA 02142, USA

[2]Melbourne Bioinformatics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3010, Australia

[3]The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia

关键词: Developmental expression;    Sodium channels;    Splice variant;   

DOI  :  

来源: DOAJ

【 摘 要 】

Genetic variation in voltage-gated sodium (NaV) channels is a significant contributor to neurodevelopmental disorders. NaV channel alpha subunits are encoded by the SCNxA family and four are predominately expressed in the brain: SCN1A, SCN2A, SCN3A, and SCN8A. Gene expression is developmentally regulated, and they are known to express functionally distinct transcript variants. Precision therapies targeting these genes and their transcript variants are currently in preclinical development, yet the developmental expression of these transcripts in the human brain is yet to be fully understood. Additionally, the functional consequences of some mutations differ depending on the studied channel isoform, suggesting differential transcript variant expression can affect disease prognoses. We characterise the expression of the four SCNxAs and their transcript variants in human, Rhesus monkey and mouse brain using publicly available RNA-sequencing data and analysis tools, demonstrating that this approach can be used to answer important biological questions of gene and transcript developmental regulation. We find that gene expression and transcript variant regulation are conserved across species at similar developmental stages and determine the developmental milestones for transcript variant expression. Our study provides a guide to researchers testing therapies and clinicians advising prognoses based on the expression of channel isoforms.

【 授权许可】

Unknown