The MAST family of genes includes MAST1, MAST2, MAST3, MAST4, and MAST-L (like). The MAST genes encode the MAST proteins which are located in neuronal cells in the developing and the mature brain. These microtubule associated serine threonine (MAST) proteins include several functional domains that may mediate interactions with other proteins (i.e. DUF, PDZ domains) or modify target proteins by phosphorylation (i.e. kinase domain). Very little is known about the molecular function of the MAST proteins but they appear to be important for proper brain development.
In 2018, a group of geneticists interested in brain malformations, identified changes in the MAST1 gene in a cohort of 6 patients with a striking brain abnormality called mega-corpus-callosum, a thickening of the tissue the connects the left and right hemispheres of the brain (Tripathy et al). These patients had a variety of other changes in their brains, as well as functional impairment ranging from global developmental delay to severe cognitive impairment with encephalopathy (brain damage). All of the patients had impaired motor abilities, including hypotonia, a stumbling gait, or the inability to stand independently. All of the patients had impaired speech, with the majority being non-verbal. Half of the patients had seizures. All of the MAST1 patients had heterozygous de novo (new) mutations, meaning the genetic changes were not present in either parent, but are present in one copy of the patients’ MAST1 genes, with the genetic change having likely occurred in developing sperm of the father or egg of the mother. In 2020, two additional patients with intellectual disability and microcephaly (small braina) were each found to have a de novo mutation in MAST1. In 2020, independent groups described heterozygous de novo mutations in MAST1 in 3 additional patients with intellectual disability/microcephaly/dysmorphic features (Hecher et al; Rodriguez-Garcia et al; Ben-Mahmoud et al). A brief literature review uncovered 3 additional patients diagnosed with intellectual disability, cerebral palsy, and/or autism and de novo variants in MAST1 (McMichael et al; Bowling et al; Gilissen et al).
In 2021, a group of geneticists focused on epilepsy, identified heterozygous de novo variants in MAST3 in a cohort of 11 patients with developmental and epileptic encephalopathy (DEE) (Spinelli et al). 8 had normal development prior to seizure onset at around 2 years of age. All patients displayed multiple seizure types. This group also demonstrated that expression of patient specific MAST3 variants, led to an increase in phosphorylation of a MAST3 target protein, ARPP-16, suggesting that the patient variants may be overactive or MAST3 “gain of function”. In 2022, 4 additional patients diagnosed with DEE were found to have heterozygous de novo variants in MAST3 (Shu et al). Large-scale genetic studies of autism uncovered 2 additional patients with variants in MAST3 (De Rubeis et al; Yuen et al).
In 2020, a genetic evaluation through the Undiagnosed Disease Network identified a de novo heterozygous variant in the MAST2 gene in Charlie Sandahl, who has developmental and epileptic encephalopathy (DEE). Since then, these doctors have identified 6 more patients with epilepsy that also have variants in MAST2.
In 2019, clinical review of a prior genetic test and Dr. Kimberly Aldinger’s review of her son Grayson’s genetic information, honed in on a de novo variant in MAST4 as the likely cause of his developmental and epileptic encephalopathy (DEE). One prior report in 2018 had linked genetic changes in MAST4 with epilepsy in 3 families (Landoulsi et al). Since then, Dr. Aldinger has connected with several geneticists internationally who are caring for patients with similar presentations that also have a de novo mutation in MAST4. Dr. Aldinger and Grayson’s father, Dr. Scott Houghtaling, continue to explore the function of MAST4, particularly as it relates to proper brain development. They use a variety of molecular genetic and cutting-edge genomic techniques, as well as cells grown in culture and zebrafish, to study MAST4 function.