A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11–q13) and refined localization of the SNRPN gene

Mutirangura, Apiwat; Jayakumar, Arumugam; Sutcliffe, James S.; Nakao, Mitsuyoshi; Mckinney, M. J.; Buiting, Karin; Horsthemke, B.; Beaudet, A. L.; Chinault, A. Craig; Ledbetter, David H.

doi:10.1016/s0888-7543(11)80011-x

Cited by 84 publications

(55 citation statements)

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“…19 A characteristic AS pattern is recognized by the presence of the 221 bp paternal band only (data not shown). Three markers within the critical region 15q11 -q13 (D15S11, D15S113 and GABRB3) 20 and at least one marker outside this region (D15S984, D15S131, D15S117, D15S115 or CYP19) were studied in patients and their parents, to distinguish between deletion and paternal uniparental disomy (data not shown).…”

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confidence: 99%

Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects

et al. 2004

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Angelman syndrome (AS) can result from either a 15q11 -q13 deletion (del), paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. Here, we describe the phenotypic and behavioral variability detected in 49 patients with different classes of deletions and nine patients with UPD. Diagnosis was made by methylation pattern analysis of exon 1 of the SNRPN-SNURF gene and by microsatellite profiling of loci within and outside the 15q11 -q13 region. There were no major phenotypic differences between the two main classes (BP1 -BP3; BP2 -BP3) of AS deletion patients, except for the absence of vocalization, more prevalent in patients with BP1 -BP3 deletions, and for the age of sitting without support, which was lower in patients with BP2 -BP3 deletions. Our data suggest that gene deletions (NIPA1, NIPA2, CYF1P1, GCP5) mapped to the region between breakpoints BP1 and BP2 may be involved in the severity of speech impairment, since all BP1 -BP3 deletion patients showed complete absence of vocalization, while 38.1% of the BP2 -BP3 deletion patients were able to pronounce syllabic sounds, with doubtful meaning. Compared to UPD patients, deletion patients presented a higher incidence of swallowing disorders (73.9% del Â 22.2% UPD) and hypotonia (73.3% del Â 28.57% UPD). In addition, children with UPD showed better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia and higher cognitive skills. As a consequence of their milder or less typical phenotype, AS may remain undiagnosed, leading to an overall underdiagnosis of the disease.

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Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects

et al. 2004

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“…Most landmarks are sequence-tagged-sites (STSs) that can be assayed using PCR (Olson et al 1989;Green and Olson 1990). An initial STS-based YAC contig was developed in 1993 with a density of about one STS per 200 kb, but this physical map contained two gaps (Mutirangura et al 1993b). Several genome-wide mapping efforts have provided additional mapping information for 15q11-q13 (Adamson et al 1995;Chumakov et al 1995;Hudson et al 1995;Sheffield et al 1995;Dib et al 1996;Schuler et al 1996;Stewart et al 1997).…”

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Integrated YAC Contig Map of the Prader–Willi/Angelman Region on Chromosome 15q11–q13 with Average STS Spacing of 35 kb

Christian

Bhatt²,

Martin³

et al. 1998

Genome Res.

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Prader-Willi syndrome and Angelman syndrome are associated with parent-of-origin-specific abnormalities of chromosome 15q11-q13, most frequently a deletion of an ∼4-Mb region. Because of genomic imprinting, paternal deficiency of this region leads to PWS and maternal deficiency to AS. Additionally, this region is frequently involved in other chromosomal rearrangements including duplications, triplications, or supernumerary marker formation. A detailed physical map of this region is important for elucidating the genes and mechanisms involved in genomic imprinting, as well as for understanding the mechanism of recurrent chromosomal rearrangments. An initial YAC contig extended from D15S18 to D15S12 and was comprised of 23 YACs and 21 STSs providing an average resolution of about one STS per 200 kb. To close two gaps in this contig, YAC screening was performed using two STSs that flank the gap between D15S18 and 254B5R and three STSs located distal to the GABRA5-149A9L gap. Additionally, we developed 11 new STSs, including seven polymorphic markers. Although several groups have developed whole-genome genetic and radiation hybrid maps, the depth of coverage for 15q11-q13 has been somewhat limited and discrepancies in marker order exist between the maps. To resolve the inconsistencies and to provide a more detailed map order of STSs in this region, we have constructed an integrated YAC STS-based physical map of chromosome 15q11-q13 containing 118 YACs and 118 STSs, including 38 STRs and 49 genes/ESTs. Using an estimate of 4 Mb for the size of this region, the map provides an average STS spacing of 35 kb. This map provides a valuable resource for identification of disease genes localized to this region as well as a framework for complete DNA sequencing.

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“…Foremost among these is allele-specific DNA methylation, which has been implicated in the mechanism by which a cell discriminates between the two parental alleles of an imprinted gene and determines which will be transcribed (Li et al 1993). Furthermore, imprinted genes are frequently linked within clusters that contain both maternally and paternally expressed genes (Zemel et al 1992;Mutirangura et al 1993;Rougeulle et al 1997;Vu and Hoffmann 1997;Wutz et al 1997). Finally, an unusual feature of these clusters is that they contain at least one imprinted gene that encodes an untranslated RNA (Brannan et al 1990;Kay et al 1993;Wevrick et al 1994;Wutz et al 1997).…”

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Igf2 imprinting does not require its own DNA methylation or H19 RNA

Jones

Levorse²,

Tilghman³

1998

Genes Dev.

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Three models have been proposed to explain the imprinting of the mouse Igf2 gene on the maternal chromosome. We ruled out the importance of DNA methylation at Igf2 by showing that silencing of Igf2 accompanying the loss of DNA methylation could be overcome by a mutation at the neighboring H19 gene that activates Igf2. By replacing the H19 structural gene with a protein-coding gene, we have ruled out a role for H19 RNA in the imprinting of Igf2. This replacement resulted in sporadic activation of the H19 promoter on the paternal chromosome without affecting the level of expression of Igf2, a finding that is inconsistent with strict promoter competition between the genes. We conclude that a transcriptional model involving access to a common set of enhancers shared between Igf2 and H19 is the most likely explanation for Igf2 imprinting.

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A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11–q13) and refined localization of the SNRPN gene

Cited by 84 publications

References 30 publications

Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects

Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects

Integrated YAC Contig Map of the Prader–Willi/Angelman Region on Chromosome 15q11–q13 with Average STS Spacing of 35 kb

Igf2 imprinting does not require its own DNA methylation or H19 RNA

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