The causes of rare diseases are being uncovered faster than ever before as genome sequencing becomes quicker and cheaper. Intriguingly, some disorders have more than one genetic basis.
One such condition is Larsen syndrome, a congenital disorder causing dislocation of large joints (shoulders, elbows, hips and knees); facial characteristics such as a prominent forehead, flattened nose and wide-set eyes; and variable other symptoms including eye problems. Mutations in three genes have already been linked to Larsen syndrome. Now, a team led by KACST’s Fowzan Alkuraya has identified a fourth, known as GZF1.
Alkuraya and his team worked with two families affected by Larsen syndrome. Hidden genetic mutations in both sides of each family came together in some of the children to produce symptoms. The symptoms differed between the families, though both had similar vision problems. The joint symptoms were less consistent.
The researchers used multiple high-tech approaches to characterize the cause of Larsen syndrome. They sequenced all the protein-coding genes in the genome, identified all the genes that had identical sequences across the affected children, and profiled the genes active in affected tissues. All the genetic mutations already known to cause Larsen syndrome were absent. Instead, the researchers found small errors, for the first time, in GZF1. Using laboratory mice, they showed that GZF1 is involved in both eye and limb development, corresponding with symptoms of the condition.
GZF1 codes for a transcription factor — a molecule controlling the activity of other genes. It contains ten small units for binding to DNA. The team hypothesized that changes in these units might prevent it from binding correctly, thereby destroying its function. Differences in the number of units affected could account for symptomatic differences between the families.
Next, the team identified downstream genes that are switched on or off by GZF1, including P3H2, a gene already implicated in severe short-sightedness. Thus, their work is beginning to elucidate the network of interacting genes causing disease in these families and those with other forms of this genetically and symptomatically heterogeneous condition.
Alkuraya hopes to extend the research to develop a mouse model of Larsen syndrome, which could be used to explore its molecular-genetic causes and even to test potential treatments. Expanding our knowledge of the genetic basis and molecular mechanisms of disease may ultimately help develop therapies for this rare but debilitating condition.
- Patel, N., Shamseldin, H.E., Sakati, N., Khan, A.O., Softa, A., et al. GZF1 mutations expand the genetic heterogeneity of Larsen syndrome. The American Journal of Human Genetics 100, 831—836 (2017). | article