Understanding the Role of Chromosome 15 in Autism
While it is thought that many genes on multiple chromosomes contribute to symptoms of autism, numerous research studies have focused on mutations of chromosome 15. A region on this chromosome, 15q11-q13, also called the “Prader Willi/Angelman Syndrome Critical Region,” contains many genes of interest that can undergo rearrangements including deletions and duplications of genetic information. These genetic mutations result in a variety of developmental problems, and individuals with duplications in this region of chromosome 15 show symptoms of pervasive developmental disorder and autism.
Recently, the Autism Tissue Program formed a collaboration with IDEAS (IsoDicentric 15, Exchange Advocacy and Support), a support group for families and professionals interested in the chromosomal conditions known as chromosome 15q duplication syndrome. A better understanding of the behavioral symptoms resulting from this chromosome abnormality will help scientists understand the role of the specific genes on this chromosome in autism spectrum disorders. In order to better explain the relationship between mutations of chromosome 15 and autism, Dr. N. Carolyn Schanen, head of human genetics research at Nemours Biomedical Research at the Alfred I. duPont Hospital for Children and principal investigator of Molecular Investigations of Duplications of Chromosome 15 in Autism, answers some of the most frequently asked questions about chromosome 15 and how these duplications contribute to autism spectrum disorders. More information about IsoDicentric 15 can be found at http://www.idic15.org/.
Could you explain what this genetic mutation is about?
Isodicentric 15, abbreviated idic(15), is one of a group of genetic conditions known as chromosome abnormalities. People with idic(15) are typically born with 47 chromosomes in each of their body cells, instead of the usual 46 found in most people. In people with idic(15), the extra chromosome is made up of a piece of chromosome number 15 which has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Occasionally, a person may have more than one extra idic(15), resulting in 48 or 49 chromosomes in all or some of their cells.
What's the connection to autism spectrum disorder?
Maternally derived duplications of chromosome 15q11-13 are the only recurrent chromosome abnormality that poses a significant risk for autism and autism related disorders.[1], [2], [3] These duplications most commonly occur in one of two forms, which collectively can be grouped under the umbrella of the dup(15) syndrome diagnosis. These include an extra isodicentric 15 chromosome or an interstitial duplication 15. The chromosome 15q11-13 region undergoes genomic imprinting and thus parent-of-origin specific gene expression. It is likely that misexpression of imprinted and biallelically expressed genes within the duplication segment leads to the autism phenotype, although the identity of the specific genes underlying susceptibility is still under investigation.
How common are duplications of chromosome 15q among individuals with autistic disorder?
Two studies that included a total of 226 patients with autism found duplications in approximately 3-5% of the patients. [4], [5] Duplications of chromosome 15q11-13 (dup15q) are the most frequently identified chromosome problem in individuals with autism.
What causes duplications of chromosome 15q to occur?
On chromosome 15, there are repeated regions that share nearly identical DNA sequence. These sequence repeats lead to duplications and copying errors by predisposing misalignment of the paired chromosomes.
What do we know about the genes in 15q11-q13?
The most commonly duplicated region is gene rich, including genes that are expressed from both paternal and maternal chromosomes as well as genes that are expressed differentially based on parent of origin of the chromosome. Because maternally derived duplications are most often associated with the autism phenotype, the two known maternally expressed genes UBE3A and ATP10A (aka ATP10C) are strong candidates. It is likely that other genes within the duplication and beyond are contributing.
The UBE3A gene is present in 4 copies in most children with idic(15) and 3 copies in most patients with interstitial duplications. Studies have shown that the extra copies of the gene are active in patients with idic(15) chromosomes. [6]
The ATP10A gene encodes an aminophospholipid ATPase. It is expressed by the brain. Its function has not been well characterized.
There are also 3 GABAA receptor genes in the region that is commonly duplicated. It is hypothesized that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions. [7] A functional GABA receptor is composed of several parts, and it is believed that expressing extra copies of some components will actually lead to fewer functional receptors. Diane C. Chugani, PhD, at Wayne State University in Detroit, Michigan is currently conducting a pilot study of Brain GABAA Receptor Abnormalities in Children with Chromosome 15q11-13 Mutations to investigate this further.
Duplication Chromosome 15q11-13 cell lines and tissue resources
The Human Genetic Cell Repository at the Coriell Institute for Medical Research in Camden, New Jersey has a total of 33 duplication 15q cell lines as of July, 2006. The majority await approval but 9 lines are currently available through their catalog for distribution. In addition, because of the relationship between individuals with genetic mutations on 15q11-14, the Autism Tissue Program encourages individuals with this disorder and their families to register for brain tissue donation. Right now, the Autism Tissue Program database also includes some dup(15) syndrome cases. IDEAS, the non-profit family support group for duplication 15q syndrome is collaborating with both Coriell and the ATP (http://www.memoriesofhope.org/) to promote these resources to families and increase the likelihood that additional samples will be available in the future.
[1]Schroer RJ, Phelan MC, Michaelis RC, et al.: Autism and maternally derived aberrations of chromosome 15q American Journal of Medical Genetics.1998;76:327-336.
[2]Wang CH, Villaca-Norat E, Papendick BD: Molecular analysis of the chromosome 15q11-q13 region in children with autism American Journal of Human Genetics.1998;63.
[3] Herzing LB, Cook EH, Jr., Ledbetter DH: Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications Hum Mol Genet.2002;11:1707-1718.
[4] Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA: Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism. Am J Hum Genet. 2005 Sep; 77(3): 377-388.
[5] Wang CH, Villaca-Norat E, Papendick BD: Molecular analysis of the chromosome 15q11-q13 region in children with autism American Journal of Human Genetics.1998;63.
[6] Herzing LB, Cook EH, Jr., Ledbetter DH: Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications Hum Mol Genet.2002;11:1707-1718.
[7] Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA: Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism. Am J Hum Genet. 2005 Sep; 77(3): 377-388.
Recently, the Autism Tissue Program formed a collaboration with IDEAS (IsoDicentric 15, Exchange Advocacy and Support), a support group for families and professionals interested in the chromosomal conditions known as chromosome 15q duplication syndrome. A better understanding of the behavioral symptoms resulting from this chromosome abnormality will help scientists understand the role of the specific genes on this chromosome in autism spectrum disorders. In order to better explain the relationship between mutations of chromosome 15 and autism, Dr. N. Carolyn Schanen, head of human genetics research at Nemours Biomedical Research at the Alfred I. duPont Hospital for Children and principal investigator of Molecular Investigations of Duplications of Chromosome 15 in Autism, answers some of the most frequently asked questions about chromosome 15 and how these duplications contribute to autism spectrum disorders. More information about IsoDicentric 15 can be found at http://www.idic15.org/.
Could you explain what this genetic mutation is about?
Isodicentric 15, abbreviated idic(15), is one of a group of genetic conditions known as chromosome abnormalities. People with idic(15) are typically born with 47 chromosomes in each of their body cells, instead of the usual 46 found in most people. In people with idic(15), the extra chromosome is made up of a piece of chromosome number 15 which has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Occasionally, a person may have more than one extra idic(15), resulting in 48 or 49 chromosomes in all or some of their cells.
What's the connection to autism spectrum disorder?
Maternally derived duplications of chromosome 15q11-13 are the only recurrent chromosome abnormality that poses a significant risk for autism and autism related disorders.[1], [2], [3] These duplications most commonly occur in one of two forms, which collectively can be grouped under the umbrella of the dup(15) syndrome diagnosis. These include an extra isodicentric 15 chromosome or an interstitial duplication 15. The chromosome 15q11-13 region undergoes genomic imprinting and thus parent-of-origin specific gene expression. It is likely that misexpression of imprinted and biallelically expressed genes within the duplication segment leads to the autism phenotype, although the identity of the specific genes underlying susceptibility is still under investigation.
How common are duplications of chromosome 15q among individuals with autistic disorder?
Two studies that included a total of 226 patients with autism found duplications in approximately 3-5% of the patients. [4], [5] Duplications of chromosome 15q11-13 (dup15q) are the most frequently identified chromosome problem in individuals with autism.
What causes duplications of chromosome 15q to occur?
On chromosome 15, there are repeated regions that share nearly identical DNA sequence. These sequence repeats lead to duplications and copying errors by predisposing misalignment of the paired chromosomes.
What do we know about the genes in 15q11-q13?
The most commonly duplicated region is gene rich, including genes that are expressed from both paternal and maternal chromosomes as well as genes that are expressed differentially based on parent of origin of the chromosome. Because maternally derived duplications are most often associated with the autism phenotype, the two known maternally expressed genes UBE3A and ATP10A (aka ATP10C) are strong candidates. It is likely that other genes within the duplication and beyond are contributing.
The UBE3A gene is present in 4 copies in most children with idic(15) and 3 copies in most patients with interstitial duplications. Studies have shown that the extra copies of the gene are active in patients with idic(15) chromosomes. [6]
The ATP10A gene encodes an aminophospholipid ATPase. It is expressed by the brain. Its function has not been well characterized.
There are also 3 GABAA receptor genes in the region that is commonly duplicated. It is hypothesized that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions. [7] A functional GABA receptor is composed of several parts, and it is believed that expressing extra copies of some components will actually lead to fewer functional receptors. Diane C. Chugani, PhD, at Wayne State University in Detroit, Michigan is currently conducting a pilot study of Brain GABAA Receptor Abnormalities in Children with Chromosome 15q11-13 Mutations to investigate this further.
Duplication Chromosome 15q11-13 cell lines and tissue resources
The Human Genetic Cell Repository at the Coriell Institute for Medical Research in Camden, New Jersey has a total of 33 duplication 15q cell lines as of July, 2006. The majority await approval but 9 lines are currently available through their catalog for distribution. In addition, because of the relationship between individuals with genetic mutations on 15q11-14, the Autism Tissue Program encourages individuals with this disorder and their families to register for brain tissue donation. Right now, the Autism Tissue Program database also includes some dup(15) syndrome cases. IDEAS, the non-profit family support group for duplication 15q syndrome is collaborating with both Coriell and the ATP (http://www.memoriesofhope.org/) to promote these resources to families and increase the likelihood that additional samples will be available in the future.
[1]Schroer RJ, Phelan MC, Michaelis RC, et al.: Autism and maternally derived aberrations of chromosome 15q American Journal of Medical Genetics.1998;76:327-336.
[2]Wang CH, Villaca-Norat E, Papendick BD: Molecular analysis of the chromosome 15q11-q13 region in children with autism American Journal of Human Genetics.1998;63.
[3] Herzing LB, Cook EH, Jr., Ledbetter DH: Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications Hum Mol Genet.2002;11:1707-1718.
[4] Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA: Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism. Am J Hum Genet. 2005 Sep; 77(3): 377-388.
[5] Wang CH, Villaca-Norat E, Papendick BD: Molecular analysis of the chromosome 15q11-q13 region in children with autism American Journal of Human Genetics.1998;63.
[6] Herzing LB, Cook EH, Jr., Ledbetter DH: Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications Hum Mol Genet.2002;11:1707-1718.
[7] Ma DQ, Whitehead PL, Menold MM, Martin ER, Ashley-Koch AE, Mei H, Ritchie MD, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Hussman JP, Gilbert JR, Pericak-Vance MA: Identification of Significant Association and Gene-Gene Interaction of GABA Receptor Subunit Genes in Autism. Am J Hum Genet. 2005 Sep; 77(3): 377-388.
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