De novo variants in MAST4 related to neurodevelopmental disorders with developmental delay and infantile spasms: Genotype-phenotype association

Abstract

ObjectiveThis study aims to prove that the de novo variants in MAST4 gene are associated with neurodevelopmental disorders (NDD) with developmental delay (DD) and infantile spasm (IS) and to determine the genotype-phenotype correlations.MethodsTrio-based exome sequencing (ES) was performed on the four families enrolled in this study. We collected and systematically reviewed the four probands’ clinical data, magnetic resonance images (MRI), and electroencephalography (EEG). We also carried out bioinformatics analysis by integrating published exome/genome sequencing data and human brain transcriptomic data.ResultsWe described four patients whose median age of seizure onset was 5 months. The primary manifestation was infantile spasms with typical hypsarrhythmia on EEG. Developmental delays or intellectual disabilities varied among the four individuals. Three de novo missense variants in MAST4 gene were identified from four families, including chr5:66438324 (c.2693T > C: p.Ile898Thr) z, chr5:66459419 (c.4412C > T: p.Thr1471Ile), and chr5:66462662 (c.7655C > G:p.Ser2552Trp). The missense variant p.Ile898Thr is mapped to the AGC-kinase C-terminal with phosphatase activity. The other variant p.Ser2552Trp is located in a phosphoserine-modified residue which may affect cell membrane stability and signal transduction. Besides, the variant p.Thr1471Ile is a recurrent site screened out in two unrelated patients. Compared to private mutations (found only in a single family or a small population) of MAST4 in the gnomAD non-neuro subset, all de novo variants were predicted to be damaging or probably damaging through different bioinformatic analyses. Significantly higher CADD scores of the variant p.Thr1471Ile indicate more deleteriousness of the recurrent site. And the affected amino acids are highly conserved across multiple species. According to the Brainspan Atlas database, MAST4 is expressed primarily in the mediodorsal nucleus of the thalamus and medial prefrontal cortex during the prenatal period, potentially contributing to embryonic brain development.ConclusionOur results revealed that the variants of MAST4 gene might lead to neurodevelopmental disorders with developmental delay and infantile spasm. Thus, MAST4 variants should be considered the potential candidate gene in patients with neurodevelopmental disorders clinically marked by infantile spasms.

Single-cell and transcriptome analysis reveals TAL cells in diabetic nephropathy

“…The MAST4 gene is predominantly expressed in the brain, particularly in the hippocampus, amygdala, and thalamus. The variants of MAST4 gene might lead to neurodevelopmental disorders with developmental delay and infantile spasm [43]. In our study, the expression of the MAST4 gene was decreased in TAL cells of diabetic nephropathy.…”

Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma

“…MAST4 is a microtubule-associated serine/threonine kinase family gene with unclear substrates, although a few have been reported, including sox9 (SRY-box9), ERM (erythromycin ribosome methylase), and Rhotekin [10][11][12]. MAST4 mutations are associated with neurodevelopmental disorders, developmental delay, and infantile spasms [13]. MAST4 maintains and enhances stemness, such as in sperm stem cells [14], suppresses mesenchymal stem cell differentiation, and promotes β-catenin nuclear translocation [15].…”

Exploring the Sheep MAST4 Gene Variants and Their Associations with Litter Size

“…Additionally, the initial documentation of the MAST4 gene was presented in the research conducted by Sun and colleagues [14]. Of great interest, functional investigations have subsequently illustrated that MAST4 plays a significant role in the pathological mechanisms concerning the central nervous system [15,16]. Moreover, recent research has indicated that the regulation of the MAST4 gene plays a vital role in maintaining spermatogonial stem cells involved in spermatogenesis, which encompasses the intricate progression of male germ cell development culminating in the intricate differentiation and maturation processes necessary for the production of functional spermatozoa [17].…”