Mutations in a non-coding gene associated with intellectual disability

Nearly 1,500 genes have been implicated in intellectual disability; Yet for most people suffering from such disabilities, the genetic causes remain unknown. Part of this may be because geneticists have focused on the wrong portions of DNA when doing their research. To address this, Ernest Turro, a biostatistician specializing in genetics, genomics and molecular diagnostics, used whole genome sequencing data from the 100,000 Genomes Project to search for areas associated with intellectual disability.

His laboratory discovered a genetic association that is the most common to date associated with a neurodevelopmental abnormality. And the gene they identified doesn’t even produce protein.

Problem with the spliceosome

Most genes contain instructions for how to make proteins. It’s true. And yet, human genes are not arranged linearly – or rather, they are arranged linearly, but not contiguously. A gene containing the instructions for the amino acids to string together to make a particular protein (hemoglobin, insulin, serotonin, albumin, estrogen, whatever protein you want) is modular. It contains part of the amino acid sequence, then a piece of DNA that is unrelated to that sequence, then some more of the protein sequence, then another random piece of DNA, going into it. back and forth until the end of the protein. It’s as if each of these paragraphs of prose were separated by an unrelated string of letters (but not by a meaningful paragraph from a different article).

In order to read this article coherently, you should delete the letters interspersed between its paragraphs. And that’s exactly what happens with genes. In order to read the gene coherently, the cell has machinery that separates the intervening sequences and connects the protein-making instructions into a continuous whole. (This does not occur in the DNA itself; it occurs in an RNA copy of the gene.) The cellular machinery is obviously called a spliceosome.

There are around a hundred proteins that make up the spliceosome. But the gene just discovered so strongly associated with neurodevelopmental disorders doesn’t encode any of them. Instead, it encodes one of five RNA molecules that are also part of the spliceosome complex and interact with RNAs that are spliced. Mutations in this gene have been found to be associated with a syndrome whose symptoms include intellectual disability, seizures, short stature, neurodevelopmental delay, drooling, motor delay, hypotonia (low muscle tone), and microcephaly. (have a small head).

Supporting data

The researchers supported their findings by examining three other databases; in each, they found more people with the syndrome who had mutations in that same gene. The mutations occur in a remarkably conserved region of the genome, suggesting that it is very important. Most of the mutations were new in those affected, meaning they were not inherited from their parents, but there was one case of a particular mutation in the gene that was inherited. Based on this, the researchers concluded that this particular variant might cause a less severe disorder than other mutations.

Many studies that search for genes associated with diseases have focused on finding catalogs of protein-coding genes. These results suggest that we may have missed important mutations due to this focus.

Natural Medicine, 2024. DOI: 10.1038/s41591-024-03085-5