Mutation responsible for low IQ

Gaia Novarino, Assistant Professor at IST Austria, together with collaborators Tim Strom (University of Bonn) and Hartmut Engels (Universität Duisburg-Essen) and their teams published a study in the European Journal of Human Genetics (doi: 10.1038/ejhg.2014.165), showing that mutations in the gene SETD5 are a relatively frequent cause of intellectual disability.

Intellectual disability, defined as an IQ of less than 70, occurs in 2-3% of the population. However, as it is an extremely heterogeneous disease, the genetic basis of intellectual disability has been hard to spot in most cases. To find genes responsible for this condition, the team of researchers studied the genes of 300 children with unexplained intellectual disability. They looked for genes that are changed between the children and their parents, who do not have an intellectual disability. If such changes occur in the same gene in different affected children, this makes it likely that the gene is involved in the disease. In two children, the researchers found new mutations in a gene called SETD5. In four other children, they found deletions of SETD5, so that a whole string of the gene sequence is missing.

Novarino and collaborators set out to find out what happens when SETD5 is mutated. They compared the normal mRNA transcripts of SETD5, which provide instructions to the cell’s protein making machinery, to mRNA transcripts of the mutated gene of patients 1 and 2. The researchers found that there were fewer SETD5 transcripts carrying the mutations compared with the unchanged transcripts. This is due to a control mechanism that eliminates defective mRNA transcripts. The result is that patients with mutations in SETD5 have less protein in their brain and thus develop intellectual disability.

An analysis of the structure of SETD5 shows that it contains two functional domains: a SET domain, which is associated with methyltransferase activity, and a PHD domain, which is usually involved in interacting with chromatin, the combination of DNA and proteins that makes up the chromosomes. This suggests that SETD5 plays a role in chromatin modification and the epigenetic regulation of gene transcription.

The gene SETD5 is found on the short arm of human chromosome 3. A syndrome in which the end of this chromosome is missing, called 3p- syndrome, is characterized by intellectual disability and other symptoms. Only three genes are likely to play a crucial role in this syndrome, one of which is SETD5.  As spontaneous changes in genes are a very rare event, the finding that two such mutations and four deletions were found in the same gene in children with intellectual disability makes a compelling case for SETD5 to be associated with the disease. Changes in SETD5 are therefore a relatively frequent cause of intellectual disability, and probably contribute significantly to the intellectual disability symptoms of 3p- syndrome.