Feb. 20, 2007 Studying mutations that give rise to a rare genetic disease, genetics researchers have identified a novel biological pathway that may have a broader role during human development, potentially in cases of mental retardation and autism.
An international team of researchers identified two genes that contribute to Cornelia deLange syndrome (CdLS), a multisystem genetic disease that affects an estimated one in 10,000 children. The disease varies from milder to more severe forms, but classically includes mental retardation, impaired growth, heart defects, feeding problems, deformed upper limbs and distinctive facial features.
In the current study, mutations in two genes of interest cause mental retardation, but with less pronounced facial features and none of the limb defects, such as missing hands or fingers, that are hallmarks of classical cases of CdLS. The genes play important roles in early development, and when mutated, cause brain abnormalities.
"Our work suggests that a subset of patients with mental retardation may have mutations in these genes, without showing the broader range of symptoms identified in diseases such as Cornelia deLange syndrome," said study leader Ian D. Krantz, M.D., a specialist in pediatric genetics at The Children's Hospital of Philadelphia. Dr. Krantz and his co-author, Laird S. Jackson, M.D., of Drexel University College of Medicine, led the study team that announced the discovery of NIPBL, the first gene known to cause CdLS, in 2004.
The current study appeared online Jan. 17 in the American Journal of Human Genetics, in advance of print publication in March 2007.
In contrast to the NIPBL gene, in which mutations cause roughly half of known CdLS cases, the researchers found that mutations in the new genes, SMC3 and SMC1A, cause only about 5 percent of CdLS cases. All three genes produce proteins called cohesin proteins. Cohesin proteins have long been known to play an important role in many species in controlling the integrity of chromosome pairs during cell division.
Recent research has unexpectedly showed that mutated genes along the cohesin pathway also cause specific abnormalities during human development. "In these cohesin complex proteins, the strongest effect seems to be in brain development," said Dr. Krantz.
Drs. Krantz and Jackson together maintain the world's largest database of patients with CdLS. The current study screened 115 patients who did not have mutations in the NIPBL gene, but who were judged to have CdLS or a milder variant of the disease, based on evaluations by clinical geneticists.
Of the 115 patients, 11 had mutations in the SMC1A or SMC3 gene. All had some degree of mental retardation, but none had limb abnormalities. Five of the 11 patients had normal height, whereas only 5 percent of patients with classic CdLS achieve normal height. The patients with the SMCIA and SMC3 mutations had milder versions of the distinctive facial features found in classical CdLS, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair.
"In many of these patients, an experienced clinician might recognize their more subtle facial features as suggestive of CdLS, but for the most part, they would only come to clinical attention for having mild to moderate mental retardation," said Matthew A. Deardorff, M.D., the first author of the study and a fellow in genetics at Children's Hospital. "This study suggests there may be other, undiscovered mutations along the cohesin pathway among patients thought to have isolated mental retardation."
"This discovery will improve the diagnosis of Cornelia deLange syndrome," added Dr. Krantz, "and also opens an avenue for investigating genetic mechanisms in broader populations of patients with abnormal brain development, in mental retardation and possibly autism as well."
Several institutes within the National Institutes of Health provided grant support for this study, along with the U.S. Cornelia deLange Syndrome Foundation, the March of Dimes, and agencies in Italy and Spain. Drs. Krantz and Deardorff are faculty members of the University of Pennsylvania School of Medicine. The study's co-authors represent ten medical institutions and seven nations: the United States, Spain, Belgium, Australia, Denmark, Canada and Italy.
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