Exploring Chromosome 15
For more than 12 years, scientists have noticed that some individuals with autism also have a chromosomal change involving a specific part of chromosome 15 (a region known as chromosome 15q11-q13). These individuals have extra copies (referred to as duplications) of this region on chromosome 15. This finding suggests that these duplications on chromosome 15 may contribute to the development of autism.
Researchers have found small segments of DNA (referred to as markers) on chromosome 15 that are seen more frequently in individuals with autism (who by chromosomal analysis have been found not to have an obvious chromosome rearrangement) than in individuals without autism. This statistical effect can only be observed when a group of individuals with autism are studied together. This finding strongly suggests that a gene that contributes to autism is in this region, but the actual gene has not yet been found.
The GABA genes
Research suggests that another region on chromosome 15 contains gene(s) that contribute to the development of autistic disorder. There are several candidate genes for autistic disorder in this region, including three GABA receptor subunit genes: GABRB3, GABRA5 and GABRG3. These genes contain instructions for making proteins that together form GABA receptors. GABA (g-aminobutyric acid) is a chemical that carries messages between nerve cells. It is in a group of chemicals called neurotransmitters. Research has not found an association between the GABRA5 gene and autistic disorder. However, research suggests that the GABRB3 and GABRG3 genes may be associated with autistic disorder. Further analysis of the GABRB3 and GABRG3 genes is needed to better understand its function and possible association with autistic disorder.
References:
- Cook EH Jr, Courchesne RY, Cox NJ, Lord C, Gonen D, Guter SJ, Lincoln A, Nix K, Haas R, Leventhal BL, Courchesne E. Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am J Hum Genet 1998; 62(5):1077-1083.
- Menold MM, Shao Y, Wolpert CM, Donnelly SL, Raiford KL, Martin ER, Ravan SA, Abramson RK, Wright HH, Delong GR, Cuccaro ML, Pericak-Vance MA, Gilbert JR. Association analysis of chromosome 15 GABAA receptor subunit genes in autistic disorder. J Neurogenet 2001; 15(3-4):245-59.
- Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R.Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002; 7(3):311-6.
- Bass MP, Menold MM, Wolpert CM, Donnelly SL, Ravan SA, Hauser ER, Maddox LO, Vance JM, Abramson RK, Wright HH, Gilbert JR, Cuccaro ML, DeLong GR, Pericak-Vance MA. Genetic studies in autistic disorder and chromosome 15. Neurogenetics 2000; 2(4):219-26.
- Martin ER, Menold MM, Wolpert CM, Bass MP, Donnelly SL, Ravan SA, Zimmerman A, Gilbert JR, Vance JM, Maddox LO, Wright HH, Abramson RK, DeLong GR, Cuccaro ML, Pericak-Vance MA.Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 2000; 96(1):43-8.
- Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP.Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium. Am J Med Genet 1999; 88(5):492-6.
UBE3A
Many researchers have reported finding changes involving a specific region (called "q11-q13") on chromosome 15 in some individuals with autistic disorder (AutD). There is also statistical evidence for susceptibility genes in this region (reviewed in Folstein and Rosen-Sheidley, 2001; Philippe et al., 1999). Together, these findings suggest that a gene associated with autistic disorder (AutD) may be located within this area on chromosome 15. Though scientists have not identified all of the genes on chromosome 15 yet, one gene located in 15q11-13, called the UBE3A gene, has been identified. UBE3A is a candidate gene for AutD because of its position in this region and its known association with Angelman Syndrome, a genetic disorder which share some symptoms in common with AutD.
Angelman Syndrome most often results from a change or "mutation" in UBE3A, or alternatively a complete absence (called a "deletion") of the copy of UBE3A inherited from the maternal side of the family. If the copy of UBE3A that was altered or missing had come from the father's side of the family, Angelman Syndrome would not occur. When gene function is affected by the sex of the parent who passed on the gene, scientists say that the gene is "imprinted." Therefore, in this case, when a person's maternal copy of the UBE3A gene doesn't function properly (due to the change in it or deletion of it), they develop Angelman syndrome.
Individuals with Angelman syndrome have mental retardation, usually do not have speech, may have episodes of inappropriate laughter (laughter unrelated to the situation) and flapping of the arms and hands. Individuals with this disorder also often have seizures, as well as small heads, ataxia (inability to coordinate muscle movements), poor muscle tone, and frequent jerky limb movements. Scientists are studying the UBE3A gene to better understand whether it may be associated with AutD.
References:
- Nurmi EL, Bradford Y, Chen Y, Hall J, Arnone B, Gardiner MB, Hutcheson HB, Gilbert JR, Pericak-Vance MA, Copeland-Yates SA, Michaelis RC, Wassink TH, Santangelo SL, Sheffield VC, Piven J, Folstein SE, Haines JL, Sutcliffe JS. Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics 2001; 77(1-2):105-13.
- Veenstra-VanderWeele J, Gonen D, Leventhal BL, Cook EH Jr. Mutation screening of the UBE3A/E6-AP gene in autistic disorder. Mol Psychiatry 1999; 4(1):64-7.
- 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(15):1707-18.
ATP10C
A newly identified gene on chromosome 15, called ATP10C, was recently studied to determine if it plays a role in the development of autism. ATP10C was considered a strong candidate gene for autism because it is located in a region of chromosome 15 that has been thought to contain a gene associated with autism. The exact function of the ATP10C gene is not known, but it is believed to produce a protein that helps transmit molecules called ions (such as calcium) between cells in the body.
To determine if the ATP10C gene was involved in autism, a team of researchers studied the region of chromosome 15 containing this gene in ten unrelated individuals with autism. The researchers were looking for changes in the sequence, or DNA code, of ATP10C that might alter how the gene works. Several variations in this gene were found. A variation in a gene does not necessarily mean that the gene will not work properly, nor that the gene is related to a particular disorder. Variations in genes can be normal. To determine if any of the gene variations were related to autism, scientists studied whether they occurred more frequently than expected by chance in a larger group of autistic individuals. They studied this in 115 individuals with autism. None of the changes identified in the original group appeared repeatedly in the group of 115 individuals, suggesting that ATP10C is unlikely to be related to autism in this group. However, the group studied was still too small to make statistical comparisons. Further studies will need to be conducted to examine ATP10C gene changes in a much larger study group of individuals with autism as well as people without autism to better understand any potential relationship between the ATP10C gene and autism.
References:
- Kim S, Herzing LBK, Veenstra-VanderWeele J, Lord C, Courchesne R, Leventhal BL, Ledbetter DH, Courchesne E, Cook EH. Mutation screening and transmission disequilibrium study of ATP10C in autism. American J Med Genet 2002); 114:137-143.
- Kashiwagi A, Meguro M, Hoshiya H, Haruta M, Ishino F, Shibahara T, Oshimura M. Predominant maternal expression of the mouse Atp10c in hippocampus and olfactory bulb. J Hum Genet. 2003; 48(4):194-8.
[back to main Genetics Overview page]
