Human Molecular Genetics Advance Access originally published online on February 2, 2005
Human Molecular Genetics 2005 14(6):785-797; doi:10.1093/hmg/ddi073
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Human Molecular Genetics, Vol. 14, No. 6 © Oxford University Press 2005; all rights reserved
Homologous pairing of 15q11–13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples
Medical Microbiology and Immunology and Rowe Program in Human Genetics, School of Medicine, University of California, Davis, CA, USA
* To whom correspondence should be addressed at: Medical Microbiology and Immunology, One Shields Avenue, Davis, CA 95616, USA. Tel: +1 5307547598; Fax: +1 5307528692; Email: jmlasalle{at}ucdavis.edu
Received December 17, 2004; Accepted January 24, 2005
Rett syndrome (RTT), caused by mutations in MECP2 (encoding methyl CpG binding protein 2), and Angelman syndrome (AS), caused by maternal deficiency of chromosome 15q11–13, are autism-spectrum neurodevelopmental disorders. MeCP2 is a transcriptional repressor of methylated genes, but MECP2 mutation does not directly affect the imprinted expression of genes within 15q11–13. We tested a potential role for MeCP2 in the homologous pairing of imprinted 15q11–13 alleles in human brain tissue and differentiated neurons by fluorescence in situ hybridization (FISH). FISH analysis of control cerebral samples demonstrated a significant increase in homologous pairing specific to chromosome 15 from infant to juvenile brain samples. Significant and specific deficiencies in the percentage of paired chromosome 15 alleles were observed in RTT, AS and autism brain samples when compared with normal controls. SH-SY5Y neuroblastoma cells also showed a significant and specific increase in the percentage of chromosome 15q11–13 paired alleles following induced differentiation in vitro. Transfection with a methylated oligonucleotide decoy specifically blocked binding of MeCP2 to the SNURF/SNRPN promoter within 15q11–13 and significantly lowered the percentage of paired 15q11–13 alleles in SH-SY5Y cells. These combined results suggest a role for MeCP2 in chromosome organization in the developing brain and provide a potential mechanistic association between several related neurodevelopmental disorders.
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