Tjitske Kleefstra, Diante Stremmelaar and Joost Kummeling, in collaboration with colleagues in an international cohort study, have shown that mutations in the SETD1A gene cause a defined rare syndrome. Interestingly, until now similar mutations in this gene have been identified in (young) adults in larger schizophrenia cohort studies. This gene therefore appears a 'neurobiological development gene', in which unique mutations cause a rare syndrome from birth, but possibly also a significantly increased risk of schizophrenia later in life. This study was published online on this week in Molecular Psychiatry.
SETD1A is a protein from an important protein complex (COMPASS) in which multiple proteins are encoded by genes harboring mutations that already have been shown to lead to specific syndromes. Interestingly, just like EHMT1, SETD1A is a histone 3 methyl transferase protein (H3K4 in the case of SETD1A; H3K9 in the case of EHMT1) and there is also an increased risk of psychotic disorders and other psychopathology in patients with Kleefstra syndrome due to EHMT1 mutations.
There are therefore indications that these types of genes and proteins (i.e. histone modifiers) are important in the development of the brain. The findings emphasize that patients with mutations in these genes though born with a rare syndrome with possibly mild (developmental) characteristics at childhood age, may well be (very) vulnerable to the development of (severe) psychopathology later in life. For this reason, it seems advisable to monitor these children carefully.
In addition to the clinical/genetic work in this study, the authors collaborated with groups in England and Canada to gain more insight into the effect of the mutations in cellular material of the patients that demonstrated abnormalities in the DNA replication mechanism. Finally, by studying the function of the Set1 ortholog on learning and memory in a fruit fly model, showed that the protein is important for these preserved functions.
Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome (Molecular Psychiatry, April 2020).