Psychologist, team first to link gene to cognitive trait

Professor of Psychology Carolyn Mervis and her group of Emory researchers are part of an interdisciplinary research team that is the first to uncover a molecular basis for a specific cognitive trait in humans. Mervis teamed up with Mark Keating, a molecular geneticist at the Howard Hughes Medical Institute at the University of Utah, and Colleen Morris, a medical geneticist at the University of Nevada School of Medicine in Las Vegas, to conduct the research that found that the deletion of a specific gene, LIM-kinase1, causes impaired cognitive development. Previously, specific genes have been linked to specific physical traits, but this is the first time a specific gene has been linked to a specific cognitive trait.

"This is an excellent example of how researchers from different fields can work together to make a significant discovery," said Mervis, who designed all the cognitive assessments in the study.

Mervis and Emory researchers Jacquelyn Bertrand, Byron Robinson and Bonnie Klein studied the cognitive abilities of people with Williams syndrome, a rare genetic disorder caused by hemizygous microdeletion on the long arm of chromosone 7. Williams syndrome causes a range of disabilities. "People with this disorder have great difficulty visualizing an object as a set of parts and then constructing a replica of the object using those parts," said Mervis. "In most people with Williams syndrome, this ability, known as visuospatial constructive cognition, is so impaired that they cannot copy even simple patterns such as a checkerboard consisting of four cubes, and they have extreme difficulty with tasks like building a model or assembling a simple piece of furniture."

A remarkable feature of Williams syndrome is a unique profile of cognitive strengths and weaknesses. Most people with Williams syndrome have mild or moderate mental retardation, with extremely impaired visuospatial constructive cognition. In contrast, their auditory short-term memory ability is often in the normal range, and their language abilities are relatively good. Williams syndrome also is associated with a unique personality profile. Most individuals with the syndrome are overly friendly to strangers and acquaintances, loquacious and overly sensitive to other people's feelings.

"One of the keys to the discovery that the gene, LIM-kinase1, causes impaired visuospatial constructive cognition was identifying individuals who had some, but not all, the features of Williams syndrome," said Mervis. The research team found these individuals have smaller deletions on chromosome 7 than those with the complete syndrome. People with partial deletions were identified because some members of their families share the same heart defect, supravalvar aortic stenosis (SVAS), that is highly correlated with Williams syndrome. In addition, some members of these families had learning difficulties in school, although their intelligence was in the normal range. These families were identified by Colleen Morris at the University of Nevada School of Medicine.

"We began our work by creating a cognitive profile of people with Williams syndrome. We found that consistently the scores of people with Williams syndrome on pattern construction (which tests visuospatial constructive cognition) were lower than their overall level of ability. In particular their pattern construction ability was lower than their auditory, short-term memory ability," said Mervis. This pattern of strengths and weaknesses is rarely seen in individuals with other disabilities.

Mervis used the Differential Ability Scales (DAS), which tests a person's strengths and weaknesses across a range of intellectual abilities, to create the profile. This profile was then used as a basis to determine how closely people who had small deletions in the Williams syndrome region shared the same cognitive strengths and weaknesses as individuals with Williams syndrome. In studies of two family groups with small deletions, Emory researchers found that family members with the deletions fit the Williams syndrome cognitive profile.

Keating and other members of his lab determined that the families with partial deletions were missing one copy of a gene known as LIM-kinase1. In one of the two families studied, only two genes were missing: elastin (which causes SVAF) and LIM-kinase1. This led Mervis, Morris and Keating to conclude that the loss of one copy of the gene LIM-kinase1 leads to impaired visuospatial constructive cognition in people with Williams syndrome. Further studies by Keating and colleagues suggested that LIM-kinase1 is an intracellular signaling molecule that is active in cells that are precursors for neurons that are essential for cognitive development.

A report of their research findings appeared in the July 12 issue of Cell, and received subsequent coverage in The New York Times, National Public Radio and Science News. The research conducted at Emory was supported by funding from the National Institutes of Health.

--Jan Gleason

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