AUTHOR=Shu Li , Xiao Neng , Qin Jiong , Tian Qi , Zhang Yanghui , Li Haoxian , Liu Jing , Li Qinrui , Gu Weiyue , Wang Pengchao , Wang Hua , Mao Xiao 

TITLE=The Role of Microtubule Associated Serine/Threonine Kinase 3 Variants in Neurodevelopmental Diseases: Genotype-Phenotype Association

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=14

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.775479

DOI=10.3389/fnmol.2021.775479

ISSN=1662-5099

ABSTRACT=<p><bold>Objective:</bold> To prove microtubule associated serine/threonine kinase 3 (<italic>MAST3</italic>) gene is associated with neurodevelopmental diseases (NDD) and the genotype-phenotype correlation.</p><p><bold>Methods:</bold> Trio exome sequencing (trio ES) was performed on four NDD trios. Bioinformatic analysis was conducted based on large-scale genome sequencing data and human brain transcriptomic data. Further <italic>in vivo</italic> zebrafish studies were performed.</p><p><bold>Results:</bold> In our study, we identified four <italic>de novo MAST3</italic> variants (NM_015016.1: c.302C &gt; T:p.Ser101Phe; c.311C &gt; T:p.Ser104Leu; c.1543G &gt; A:p.Gly515Ser; and c.1547T &gt; C:p.Leu516Pro) in four patients with developmental and epileptic encephalopathy (DEE) separately. Clinical heterogeneities were observed in patients carrying variants in domain of unknown function (DUF) and serine-threonine kinase (STK) domain separately. Using the published large-scale exome sequencing data, higher CADD scores of missense variants in DUF domain were found in NDD cohort compared with gnomAD database. In addition, we obtained an excess of missense variants in DUF domain when compared autistic spectrum disorder (ASD) cohort with gnomAD database, similarly an excess of missense variants in STK domain when compared DEE cohort with gnomAD database. Based on Brainspan datasets, we showed that <italic>MAST3</italic> expression was significantly upregulated in ASD and DEE-related brain regions and was functionally linked with DEE genes. In zebrafish model, abnormal morphology of central nervous system was observed in <italic>mast3a/b</italic> crispants.</p><p><bold>Conclusion:</bold> Our results support the possibility that <italic>MAST3</italic> is a novel gene associated with NDD which could expand the genetic spectrum for NDD. The genotype-phenotype correlation may contribute to future genetic counseling.</p>