NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation

The X-chromosome carries a number of genes that are involved in a child's intellectual development. One of these genes encodes a protein called MeCP2, which is important for brain function after birth. Mutations in the MECP2 gene cause a disorder known as Rett syndrome. At around 18 months of age, affected children begin to lose the cognitive and motor skills that they had previously acquired. Individuals with extra copies of this gene also show cognitive impairments. For both diseases, individuals with levels of the MeCP2 protein that are the most different from those found in healthy individuals also show the most severe symptoms. To produce the protein that is encoded by a particular gene, enzymes inside the cell must first make a copy of that gene using a molecule called messenger ribonucleic acid (or mRNA). This mRNA is then used as a template to assemble the protein itself. In the case of MECP2, two different mRNA templates are produced: a long version and a short version. A gene called NUDT21 makes a protein that regulates whether the long or short version of MECP2 mRNA is made. Gennarino, Alcott et al. have now discovered that people with too many, or too few, copies of the NUDT21 gene have intellectual disabilities and altered levels of MeCP2 protein. Specifically, individuals with extra copies of NUDT21—and thus higher levels of the corresponding protein—produce more of the long MECP2 mRNA. The production of proteins from this long mRNA is less efficient than from the short mRNA; therefore, these individuals have lower levels of MeCP2 protein. The opposite is true for individuals who lack a copy of the NUDT21 gene. To confirm these data, Gennarino, Alcott et al. grew cells in the laboratory from patients with extra copies of the NUDT21 gene and found that reducing the production of its protein returned the levels of the MeCP2 protein back to normal. These findings show that alterations in the NUDT21 gene cause changes in the level of MeCP2 protein in cells and leads to neuropsychiatric diseases.