Abstract
Objective: To prove microtubule associated serine/threonine kinase 3 (MAST3) gene is associated with neurodevelopmental diseases (NDD) and the genotype-phenotype correlation.Methods: 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 in vivo zebrafish studies were performed.Results: In our study, we identified four de novo MAST3 variants (NM_015016.1: c.302C > T:p.Ser101Phe; c.311C > T:p.Ser104Leu; c.1543G > A:p.Gly515Ser; and c.1547T > 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 MAST3 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 mast3a/b crispants.Conclusion: Our results support the possibility that MAST3 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.
Highlights
Microtubule associated serine/threonine kinase 3 [MAST3 (MIM 612258)] gene belongs to microtubule-associated serine/threonine kinase (MAST) family which harbors conserved protein domains including a central microtubule-associated serine-threonine kinase domain (STK) flanked by domain of unknown function (DUF) (Hain et al, 2014)
Together with bioinformatic analyses and functional studies on zebrafish model, our study indicated that MAST3 variants may be related to variable neurodevelopmental phenotypes from intellectual disability (ID) with epilepsy to ID with autistic spectrum disorder (ASD)
De novo Microtubule Associated Serine/Threonine Kinase 3 Missense Variants in Domain of Unknown Function and Serine-Threonine Kinase Domain Exhibit Excess in Neurodevelopmental Diseases In our study, we found a significant enrichment of MAST3 variants via analysis of de novo variants by two statistic models
Summary
Microtubule associated serine/threonine kinase 3 [MAST3 (MIM 612258)] gene belongs to microtubule-associated serine/threonine kinase (MAST) family which harbors conserved protein domains including a central microtubule-associated serine-threonine kinase domain (STK) flanked by domain of unknown function (DUF) (Hain et al, 2014). In MAST gene family, MAST1 gene has been reported to cause neurodevelopmental diseases (NDD). The representative clinical phenotypes of the patients are mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCH-CM) (MIM:618273) (McMichael et al, 2015; Tripathy et al, 2018; Ben-Mahmoud et al, 2020; Rodriguez-Garcia et al, 2020). Spinelli et al (2021) reported that patients with de novo variants in STK domain of MAST3 gene showed concomitant developmental and epileptic encephalopathy (DEE) phenotypes (Spinelli et al, 2021) MAST2-4 genes have never been reported to be associated with neurological disorders until 2021. Spinelli et al (2021) reported that patients with de novo variants in STK domain of MAST3 gene showed concomitant developmental and epileptic encephalopathy (DEE) phenotypes (Spinelli et al, 2021)
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