Gender influences monoallelic expression of ATP10A in human brain. Hum Genet

Medical Microbiology and Immunology, Rowe Program in Human Genetics, School of Medicine, University of California, One Shields Ave, Davis, CA 95616, USA.
Human Genetics (Impact Factor: 4.82). 09/2008; 124(3):235-42. DOI: 10.1007/s00439-008-0546-0
Source: PubMed


Human chromosome 15q11-13 and the syntenic region of mouse chromosome 7 contain multiple imprinted genes necessary for proper neurodevelopment. Due to imprinting, paternal 15q11-13 deficiencies lead to Prader-Willi syndrome (PWS) while maternal 15q11-13 deficiencies cause Angelman syndrome (AS). The mechanisms involved in parental imprinting of this locus are conserved between human and mouse, yet inconsistencies exist in reports of imprinting of the maternally expressed gene Atp10a/ATP10A. Excess maternal 15q11-13 dosage often leads to autism-spectrum disorder therefore further investigation to characterize the true imprinting status of ATP10A in humans was warranted. In this study, we examined allelic expression of ATP10A transcript in 16 control brain samples, and found that 10/16 exhibited biallelic expression while only 6/16 showed monoallelic expression. Contrary to the expectation for a maternally expressed imprinted gene, quantitative RT-PCR revealed significantly reduced ATP10A transcript in Prader-Willi syndrome brains with two maternal chromosomes due to uniparental disomy (PWS UPD). Furthermore, a PWS UPD brain sample with monoallelic ATP10A expression demonstrated that monoallelic expression can be independent of imprinting. Investigation of factors that may influence allelic ATP10A expression status revealed that gender has a major affect, as females were significantly more likely to have monoallelic ATP10A expression than males. Regulatory sequences were also examined, and a promoter polymorphism that disrupts binding of the transcription factor Sp1 also potentially contributes to allelic expression differences in females. Our results show that monoallelic expression of human ATP10A is variable in the population and is influenced by both gender and common genetic variation.

Download full-text


Available from: Janine M Lasalle, Oct 05, 2015
25 Reads
  • Source
    • "Studies in mouse models also indicate that ATP10A is not expressed exclusively from the maternal allele in neurons as previously proposed [DuBose, Johnstone, Smith, Hallett, & Resnick, 2010]. Furthermore, studies using human brain samples indicate that ATP10A expression is predominantly biallelic in brain and is influenced by both gender and genetic variation in the population [Hogart, Patzel, & LaSalle, 2008]. Here we propose that maternal interstitial duplications of the region between BP2 and BP3 are sufficient to produce an autism phenotype due most likely to overexpression of the maternally expressed UBE3A gene on the duplicated chromosomal segment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chromosomal copy number variants (CNV) are the most common genetic lesion found in autism. Many autism-associated CNVs are duplications of chromosome 15q. Although most cases of interstitial (int) dup(15) that present clinically are de novo and maternally derived or inherited, both pathogenic and unaffected paternal duplications of 15q have been identified. We performed a phenotype/genotype analysis of individuals with interstitial 15q duplications to broaden our understanding of the 15q syndrome and investigate the contribution of 15q duplication to increased autism risk. All subjects were recruited solely on the basis of interstitial duplication 15q11.2-q13 status. Comparative array genome hybridization was used to determine the duplication size and boundaries while the methylation status of the maternally methylated small nuclear ribonucleoprotein polypeptide N gene was used to determine the parent of origin of the duplication. We determined the duplication size and parental origin for 14 int dup(15) subjects: 10 maternal and 4 paternal cases. The majority of int dup(15) cases recruited were maternal in origin, most likely due to our finding that maternal duplication was coincident with autism spectrum disorder. The size of the duplication did not correlate with the severity of the phenotype as established by Autism Diagnostic Observation Scale calibrated severity score. We identified phenotypes not comprehensively described before in this cohort including mild facial dysmorphism, sleep problems and an unusual electroencephalogram variant. Our results are consistent with the hypothesis that the maternally expressed ubiquitin protein ligase E3A gene is primarily responsible for the autism phenotype in int dup(15) since all maternal cases tested presented on the autism spectrum. Autism Res 2013, ●●: ●●-●●. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.
    Autism Research 08/2013; 6(4). DOI:10.1002/aur.1284 · 4.33 Impact Factor
  • Source
    • "Snrpn normally displays imprinted expression in all tissues [40], while Ube3a has imprinted expression only in the brain [41-43]. There are conflicting reports regarding the imprinted status of Atp10a in both human beings [44-46] and mice [47-49]. The inclusion of Smchd1MommeD1/+ female embryos in this analysis demonstrated that haploinsufficiency for Smchd1 was not sufficient to cause detectable disruption of expression for the affected genes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Smchd1 is an epigenetic modifier essential for X chromosome inactivation: female embryos lacking Smchd1 fail during midgestational development. Male mice are less affected by Smchd1-loss, with some (but not all) surviving to become fertile adults on the FVB/n genetic background. On other genetic backgrounds, all males lacking Smchd1 die perinatally. This suggests that, in addition to being critical for X inactivation, Smchd1 functions to control the expression of essential autosomal genes. Using genome-wide microarray expression profiling and RNA-seq, we have identified additional genes that fail X inactivation in female Smchd1 mutants and have identified autosomal genes in male mice where the normal expression pattern depends upon Smchd1. A subset of genes in the Snrpn imprinted gene cluster show an epigenetic signature and biallelic expression consistent with loss of imprinting in the absence of Smchd1. In addition, single nucleotide polymorphism analysis of expressed genes in the placenta shows that the Igf2r imprinted gene cluster is also disrupted, with Slc22a3 showing biallelic expression in the absence of Smchd1. In both cases, the disruption was not due to loss of the differential methylation that marks the imprint control region, but affected genes remote from this primary imprint controlling element. The clustered protocadherins (Pcdhalpha, Pcdhbeta, and Pcdhgamma) also show altered expression levels, suggesting that their unique pattern of random combinatorial monoallelic expression might also be disrupted. Smchd1 has a role in the expression of several autosomal gene clusters that are subject to monoallelic expression, rather than being restricted to functioning uniquely in X inactivation. Our findings, combined with the recent report implicating heterozygous mutations of SMCHD1 as a causal factor in the digenically inherited muscular weakness syndrome facioscapulohumeral muscular dystrophy-2, highlight the potential importance of Smchd1 in the etiology of diverse human diseases.
    Epigenetics & Chromatin 07/2013; 6(1):19. DOI:10.1186/1756-8935-6-19 · 5.33 Impact Factor
  • Source
    • "Complete Ube3a antisense transcription would be expected to block Pol II from transcribing the sense transcript, resulting in paternally imprinted Ube3a only in mature neurons exhibiting full decondensation of Snrpn-Ube3a. Cellular heterogeneity and variable processivity of Pol II beyond the 3 0 end of Ube3a on the paternal allele may also explain the variable imprinting status of Atp10a [Kashiwagi et al., 2003; Kayashima et al., 2003a,b; Hogart et al., 2008]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic mechanisms play essential roles in mammalian neurodevelopment and genetic mutations or chromosomal deletions or duplications of epigenetically regulated loci or pathways result in several important human neurodevelopmental disorders. Postnatal mammalian neurons have among the most structured and dynamic nuclear organization of any cell type. Human chromosome 15q11-13 is an imprinted locus required for normal neurodevelopment and is regulated by a plethora of epigenetic mechanisms in neurons, including multiple noncoding RNAs, parentally imprinted transcription and histone modifications, large-scale chromatin decondensation, and homologous pairing in mature neurons of the mammalian brain. Here, we describe the multiple epigenetic layers regulating 15q11-13 gene expression and chromatin dynamics in neurons and propose a model of how noncoding RNAs may influence the unusual neuronal chromatin structure and dynamics at this locus. We also discuss the need for improved neuronal cell culture systems that model human 15q11-13 and other neurodevelopmental disorders with epigenetic bases in order to test the mechanisms of chromatin dynamics and nuclear organization in neurons. Induced pluripotent stem cells and other stem cell technologies hold promise for improved understanding of and therapeutic interventions for multiple human neurodevelopmental disorders.
    Journal of Cellular Biochemistry 02/2011; 112(2):365-73. DOI:10.1002/jcb.22958 · 3.26 Impact Factor
Show more