The Journal of Young Investigators: An Undergraduate, Peer-Reviewed Science Journal
Volume 20, Issue 3. September 2010
Newly Discovered Gene May Lead to Better Understanding of Mental Retardation
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23 February 2007 -
In a study that appeared in the January 17th issue of the American Journal of Human Genetics, an international group of scientists have identified two genes associated with Cornelia deLange syndrome (CdLS) that may also be associated with a lesser form of the disease. Mutations in these two genes were shown to cause a less severe form of mental retardation. This discovery may provide a better understanding of the biological pathway of mental retardation and provide a better way to diagnose CdLS.
The two genes, SMC3 and SMC1A, along with the NIPBL gene in which mutations cause about half of all CdLS cases, produce cohesion proteins. These cohesion proteins are known to be important in many species in maintaining proper chromosome pairs during cell division. The genes are known to play an important role in early brain development, and mutations in these genes were shown to cause defects of the brain. While the role of cohesion proteins in cell division has long been known, it has only recently been discovered that mutated genes in the cohesion pathway can cause specific defects during human development.
The leader of the study was Ian D. Krantz, M.D., a specialist in pediatric genetics at The Children’s Hospital of Philadelphia. He stated that people with certain forms of mental retardation may in fact have a defect in these genes, judging by the fact that their symptoms are not as severe as though with full CdLS.
"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," Dr. Krantz stated.
CdLS is a congenital disease that affects many systems whose effects vary widely in the form of physical defects, mental retardation, heart impairments, deformed upper limbs, affected growth, feeding problems, and specific facial features. In the study, mutations in the two SMC3 and SMC1A genes caused mental retardation, but showed less severe facial features and no physical defects.
The study used 115 patients who had no mutation in the NIPBL gene and were judged to have CdLS or a less defective form of the disease. Of the 115 patients used in the study, 11 had mutations in one of the two genes. All of the patients had mental retardation, while none had physical defects. Whereas 5% of patients with classic CdLS have normal height, 5 of the 11 patients in the study with mutations in the two genes had normal height. The patients with defects in the two genes generally had milder forms of the standard facial feature defects found in those with CdLS.
"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 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," said Dr. Krantz.
Dr. Krantz, along with Dr. Laird Jackson, M.D., of Drexel University College of Medicine, led the study that discovered the NIPBL gene, the first gene known to cause CdLS, in 2004. They currently run the world largest database of patients with CdLS.
Written by Falishia Sloan
The two genes, SMC3 and SMC1A, along with the NIPBL gene in which mutations cause about half of all CdLS cases, produce cohesion proteins. These cohesion proteins are known to be important in many species in maintaining proper chromosome pairs during cell division. The genes are known to play an important role in early brain development, and mutations in these genes were shown to cause defects of the brain. While the role of cohesion proteins in cell division has long been known, it has only recently been discovered that mutated genes in the cohesion pathway can cause specific defects during human development.
The leader of the study was Ian D. Krantz, M.D., a specialist in pediatric genetics at The Children’s Hospital of Philadelphia. He stated that people with certain forms of mental retardation may in fact have a defect in these genes, judging by the fact that their symptoms are not as severe as though with full CdLS.
"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," Dr. Krantz stated.
CdLS is a congenital disease that affects many systems whose effects vary widely in the form of physical defects, mental retardation, heart impairments, deformed upper limbs, affected growth, feeding problems, and specific facial features. In the study, mutations in the two SMC3 and SMC1A genes caused mental retardation, but showed less severe facial features and no physical defects.
The study used 115 patients who had no mutation in the NIPBL gene and were judged to have CdLS or a less defective form of the disease. Of the 115 patients used in the study, 11 had mutations in one of the two genes. All of the patients had mental retardation, while none had physical defects. Whereas 5% of patients with classic CdLS have normal height, 5 of the 11 patients in the study with mutations in the two genes had normal height. The patients with defects in the two genes generally had milder forms of the standard facial feature defects found in those with CdLS.
"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 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," said Dr. Krantz.
Dr. Krantz, along with Dr. Laird Jackson, M.D., of Drexel University College of Medicine, led the study that discovered the NIPBL gene, the first gene known to cause CdLS, in 2004. They currently run the world largest database of patients with CdLS.
Written by Falishia Sloan
Journal of Young
Investigators. 2008. Volume 0.
Copyright © 2008 by Falishia Sloan and and JYI. All rights reserved.
Copyright © 2008 by Falishia Sloan and and JYI. All rights reserved.