Around the CdLS Foundation office, we err on the side of silliness when remembering names of genes and other scientific facts. You can’t expect too much from a group of social workers, some liberal arts majors and a part-time opera singer. For instance, when the second gene was found, no one could remember its name (SMC1A), so it became Start My Car. And then there’s sister chromatid cohesion. We like to picture two nuns holding our genes together.
Obviously, it’s best we leave the scientific work to the experts, like Dr. Matthew Deardorff, a member of our Clinical Advisory Board and the research team at the Children’s Hospital of Philadelphia (CHOP). So, we thought we’d ask him to talk a little about the latest gene finding, and what it means. Read on below. –MM
Recently, our group at CHOP in collaboration with a number of families and physicians from around the world were able to better understand the cause of CdLS in some patients by analyzing two additional genes, SMC1A and SMC3. Last April, the SMC1A gene (a.k.a. SMC1L1) was discovered by our Italian colleagues, Drs. Antonio Musio and Angelo Selicorni.
Since we have the good fortune of having so many families participating in our research, we were able to test more than 100 individuals who did not show a change in NIPBL, the first gene found to cause CdLS (and found in more than 50 percent of affected individuals). We found SMC1A gene changes in 14 individuals, or about 5% of patients.
It turns out that quite a bit of work has been done over the last 20 years to understand how SMC1A works—most of it in bacteria and yeast. Follow-up work has shown that similar systems function in human cells also. Specifically, SMC1A and a number of other proteins are involved in one aspect of holding chromosomes pairs together (sister chromatid cohesion). We thought that maybe other genes that function in this process might also cause CdLS. So, we looked at a number of genes in about 100 patients and found a mutation in SMC1A’s partner, SMC3.
When we looked carefully at the features of the patients with changes in these two genes, something was quite apparent: all of these patients fit into a “milder” category of CdLS. None had severe limb differences, and all had learned to walk and talk. Even more notable was that as several of these individuals aged, the features that had enabled them to be diagnosed with CdLS as younger patients were much less apparent.
We have begun to wonder whether changes in these genes may cause not only mild CdLS, but may also be responsible for causing mental retardation in patients that we would not recognize as CdLS. While SMC1A and SMC3 may in the end prove to cause CdLS in only a small minority of patients, finding changes in these genes has clearly focused our attention on understanding how sister chromatid cohesion causes children to be born with CdLS.