The Prader-Willi/Angelman Critical Region (PWACR; Chromosome 15q11-13) is of interest as a potential locus for genes conferring susceptibility to autism spectrum disorders (ASD). This report describes a female proband referred for evaluation of a possible ASD. Genetic analyses indicated that the proband, her father and one of her sisters, carried a paternally derived interstitial duplication involving 15q11-13. The proband showed evidence of ASD (PDD-NOS), borderline mental retardation, mild hypotonia and joint laxity. Her father and her sister were of normal intelligence and neither was thought to have an ASD, although speech/language difficulties and some autistic type behaviours were reported to have been present early in the development of the sister. This is one of the first reports of a child with a paternal duplication and an autism spectrum disorder. More research is required to determine whether paternally derived duplications that involve 15q11-13 are associated with developmental impairments.
" variable degrees of developmental delay [ Bolton et al . , 2001 ] , while only a few cases of paternally transmitted 15q duplication have been reported , and these cases primarily presented with no phenotype or speech delay and behavior problems [ C . E . Browne et al . , 1997 ; Cook et al . , 1997 ; Mao et al . , 2000 ; Mohandas et al . , 1999 ; Veltman et al . , 2005 ] . The prevailing hypothesis is that maternal duplications are associated with the ASD phenotype based mainly on individual case studies , while there is still an insufficient number of cases to establish the influence of paternal int dup ( 15 ) on the ASD phenotype [ Hogart , Wu , LaSalle , & Schanen , 2010 ] . It is important to note"
"cause AS, maternal duplications of this region consistently result in an autism phenotype (reviewed in ). A key indicator that the maternally expressed UBE3A gene is primarily responsible for the autism phenotype in individuals with 15q duplication is the fact that paternal duplications, where the UBE3A gene is silent on the duplicated allele, can often be non-pathogenic or do not involve a clear ASD phenotype –. A recent mouse model of duplication 15q autism confirms that elevated dosage of the UBE3A gene is sufficient to produce autism-like behaviors in a mouse model of 15q duplication syndrome lending additional support to the hypothesis that elevation of UBE3A levels in the brain is the primary cause of autism in duplication 15q syndrome . "
[Show abstract][Hide abstract] ABSTRACT: The molecular defects associated with Angelman syndrome (AS) and 15q duplication autism are directly correlated to expression levels of the E3 ubiquitin ligase protein UBE3A. Here we used Drosophila melanogaster to screen for the targets of this ubiquitin ligase under conditions of both decreased (as in AS) or increased (as in dup(15)) levels of the fly Dube3a or human UBE3A proteins. Using liquid phase isoelectric focusing of proteins from whole fly head extracts we identified a total of 50 proteins that show changes in protein, and in some cases transcriptional levels, when Dube3a fluctuates. We analyzed head extracts from cytoplasmic, nuclear and membrane fractions for Dube3a regulated proteins. Our results indicate that Dube3a is involved in the regulation of cellular functions related to ATP synthesis/metabolism, actin cytoskeletal integrity, both catabolism and carbohydrate metabolism as well as nervous system development and function. Sixty-two percent of the proteins were >50% identical to homologous human proteins and 8 have previously be shown to be ubiquitinated in the fly nervous system. Eight proteins may be regulated by Dube3a at the transcript level through the transcriptional co-activation function of Dube3a. We investigated one autism-associated protein, ATPα, and found that it can be ubiquitinated in a Dube3a dependent manner. We also found that Dube3a mutants have significantly less filamentous actin than wild type larvae consistent with the identification of actin targets regulated by Dube3a. The identification of UBE3A targets is the first step in unraveling the molecular etiology of AS and duplication 15q autism.
PLoS ONE 04/2013; 8(4):e61952. DOI:10.1371/journal.pone.0061952 · 3.23 Impact Factor
"Autistic phenotype associated with 15q11-13 duplication, usually believed that maternal origin, UBE3A is involved [39–46]. Although maternal locus supposed to critical, paternally inherited patients had also developmental delay [44, 46–49]. Clinical reports have been accumulating but no mechanism has been addressed. "
[Show abstract][Hide abstract] ABSTRACT: The development of genetic technologies has led to the identification of several copy number variations (CNVs) in the human genome. Genome rearrangements affect dosage-sensitive gene expression in normal brain development. There is strong evidence associating human psychiatric disorders, especially autism spectrum disorders (ASDs) and schizophrenia to genetic risk factors and accumulated CNV risk loci. Deletions in 1q21, 3q29, 15q13, 17p12, and 22q11, as well as duplications in 16p11, 16p13, and 15q11-13 have been reported as recurrent CNVs in ASD and/or schizophrenia. Chromosome engineering can be a useful technology to reflect human diseases in animal models, especially CNV-based psychiatric disorders. This system, based on the Cre/loxP strategy, uses large chromosome rearrangement such as deletion, duplication, inversion, and translocation. Although it is hard to reflect human pathophysiology in animal models, some aspects of molecular pathways, brain anatomy, cognitive, and behavioral phenotypes can be addressed. Some groups have created animal models of psychiatric disorders, ASD, and schizophrenia, which are based on human CNV. These mouse models display some brain anatomical and behavioral abnormalities, providing insight into human neuropsychiatric disorders that will contribute to novel drug screening for these devastating disorders.
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