Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3

Abstract

Autism is a common neurodevelopmental disorder of complex genetic etiology. Rett syndrome, an X-linked dominant disorder caused by MECP2 mutations, and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. MECP2 encodes methyl-CpG-binding protein 2 that acts as a transcriptional repressor for methylated gene constructs but is surprisingly not required for maintaining imprinted gene expression. Here, we test the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods were used including automated quantitation of immunofluorescence and in situ hybridization by laser scanning cytometry on tissue microarrays, immunoblot and TaqMan PCR. The results demonstrated significant defects in UBE3A/E6AP expression in two different Mecp2 deficient mouse strains and human Rett, Angelman and autism brains compared with controls. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. A non-imprinted gene from 15q11-q13, GABRB3, encoding the beta3 subunit of the GABAA receptor, also showed significantly reduced expression in multiple Rett, Angelman and autism brain samples, and Mecp2 deficient mice by quantitative immunoblot. These results suggest an overlapping pathway of gene dysregulation within 15q11-q13 in Rett, Angelman and autism and implicate MeCP2 in the regulation of UBE3A and GABRB3 expressions in the postnatal mammalian brain.

Advances in behavioral genetics: mouse models of autism

“…64 Given the possible contribution of epigenetic factors to autism, researchers have examined interactions involving genes from imprinted regions of chromosome 15q. There has been some evidence that Mecp2 regulates Ube3A and Gabrb3 expression in the mouse model for Rett syndrome, 87,344 but this finding has been inconsistent. 345 There are also reports that Mecp2 plays a role in the regulation of Bdnf levels.…”

“…Reduced expression of UBE3A in cerebral tissue has been reported for autism and Rett syndrome, as well as AS, albeit in a small number of samples. 87 Mice with maternal deficiency of Ube3a (mÀ/p þ ) have deficits in motor coordination and context-dependent fear conditioning, [88][89][90] reduced spatial learning in the Morris water maze task, 88,90 and enhanced seizure susceptibility. 88,89 More severe symptoms in AS may involve the contribution of other genes in the 15q11-13 region, including GABRB3, which encodes the b3-subunit of the g-aminobutyric acid (GABA) type A receptor.…”

“…As previously noted, AS is associated with anomalies in the region of chromosome 15q11-13, which includes GABRB3 and a cluster of other GABA-related genes. Samaco et al 87 have shown that the expression of GABRB3 in brain is deficient in subjects with AS, autism or Rett syndrome, but not in subjects with Down syndrome. Reduced expression of specific GABA(A) receptor subunits [120][121][122] and aberrant GABAergic neural circuitry 123 have been reported in the FXS model mouse.…”

Neural stem cells: mechanisms and modeling

“…Although Rett syndrome is still a monogenetic disease and its clinical symptoms have been well recapitulated in mouse models, the modeling of Rett syndrome with iPSCs provides a compelling precedent for this type of research. Rett syndrome is characterized by decelerated childhood development, and its clinical symptoms include regression of acquired skills, loss of speech, stereotypical movements, microcephaly, seizures, autistic characteristics and mental retardation (Segawa, 2001;Samaco et al, 2005). Rett syndrome results from mutations in the X-chromosome-linked MeCP2 gene, which regulates gene expression through modulating DNA methylation (Akbarian, 2003;Chahrour and Zoghbi, 2007).…”

A powerful parent-of-origin effects test for qualitative traits incorporating control children in nuclear families

“…For some complex diseases, such as Beckwith-Wiedemann, Prader-Willi and Angelman syndromes, diabetes and schizophrenia, imprinting effects have been demonstrated or hypothesized to have an important role. [2][3][4][5][6][7][8][9][10] Further, incorporating information on imprinting effects into association analysis could improve the test power. 11 On the other hand, genomic imprinting has been largely examined in analyses of complex traits through testing for parent-of-origin effects of alleles.…”