This study describes how a combination of sequencing and mouse models were used to identify the gene responsible for a brain developmental disorder seen in four patients. The study also shows that the biology uncovered in the mouse model helps to understand the symptoms in patients.
The work highlights how animal models are a complementary approach for determining the causal genes and for understanding the biology behind genetic disorders.
Researchers have defined the gene responsible for a rare developmental disorder in children. The team showed that rare variation in a gene involved in brain development causes the disorder. This is the first time that this gene, UBE3B, has been linked to a disease.
By using a combination of research in mice and sequencing the DNA of four patients with the disorder, the team showed that disruption of this gene causes symptoms including brain abnormalities and reduced growth, highlighting the power of mouse models for understanding the biology behind rare diseases
"Ubiquitination, the biological pathway UBE3B is involved in, is crucial in neurodevelopment," says Dr Guntram Borck, lead author from the University of Ulm. "We have studied several patients with this rare condition, and by sequencing the coding regions of the genome of these patients we found mutations implicating the gene UBE3B. This result was confirmed by studies performed in mice by our collaborators at the Sanger Institute.
At the Sanger researchers deleted the gene in mice and found that they had symptoms that were quite similar to those in the patients with UBE3B mutations including; reduced body weight and size, and reduced size of the brain.
The studies in mice also uncovered other defects underlying the disorder. Mice with the gene deletion had reduced cholesterol levels, a symptom that was seen by the team in three of the patients. This observation suggests that a defect in cholesterol metabolism is associated with this syndrome.