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Query: UNIPROT:P06889 (Mol)
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Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders associated with deletions of proximal 15q (q11-q13) of different parental origin. Yeast artificial chromosome (YAC) clones were isolated for 9 previously mapped DNA probes from this region, and for one newly derived marker, LS6-1 (D15S113). A YAC contig of 1-1.5 Mb encompassing four markers (ML34, IR4-3R, PW71, and TD189-1) was constructed. Multi-color fluorescence in situ hybridization (FISH) analysis of interphase nuclei was combined with YAC contig information to provide the following order of markers: cen-IR39-ML34-IR4-3R-PW71-TD189-1-LS6++ +-1-TD3-21-GABRB3-IR10-1-CMW1-tel. FISH analysis was performed on 8 cases of PWS and 3 cases of AS, including 5 patients with normal karyotypes. All eleven patients were deleted for YACs in the interval from IR4-3R to GABRB3. On the proximal side of the deletion interval, 10/10 breakpoints fell within a single ML34 YAC of 370 kb. On the distal side, 8/9 breakpoints fell within a single IR10-1 YAC of 200 kb. These results indicate a striking consistency in the location of the proximal and distal breakpoints in PWS and AS patients. FISH analysis on a previously reported case of familial AS confirmed a submicroscopic deletion including YACs corresponding to LS6-1, TD3-21 and GABRB3 and supports the separation of the PWS and AS critical regions. Since these three YACs do not overlap each other, the minimum size of the AS critical region is > or = 650 kb.
Hum Mol Genet 1992 Sep
PMID:Molecular dissection of the Prader-Willi/Angelman syndrome region (15q11-13) by YAC cloning and FISH analysis. 136 1

Meiotic recombination is a specifically timed and regulated process which does not occur randomly throughout the genome, but tends to be clustered in 'hotspots'. There is extensive evidence that recombination rate is influenced by chromatin conformation and that events are primarily initiated at gene promoter regions. In an effort to determine the pattern of chromatin condensation and recombination at meiosis in an imprinted region, fine scale genetic mapping in the approximately 4 Mb Prader-Willi/Angelman syndrome deletion region was undertaken. The results indicate that the male-female recombination ratio can vary significantly over short regions. A male recombination hotspot is localized to between the 3' end of GABRA5 and D15S156, which is adjacent to but outside the putative AS/PWS imprinted regions. In addition, a region of relatively high recombination in females is observed between D15S128 and D15S97, which spans a domain of paternal allele-specific transcription implicated in the Prader-Willi syndrome. It is inferred that the inactivation and relative condensation of this latter region on the maternal chromosome occurs as a post-meiotic modification.
Hum Mol Genet 1995 May
PMID:Sex-specific meiotic recombination in the Prader--Willi/Angelman syndrome imprinted region. 763 38

Chromosomal changes through pericentric inversions play an important role in the origin of species. Certain pericentric inversions are too minute to be detected cytogenetically, thus hindering the complete reconstruction of hominoid phylogeny. The advent of the fluorescence in situ hybridization (FISH) technique has facilitated the identification of many chromosomal segments, even at the single gene level. Therefore the cosmid probe for Prader-Willi (PWS)/Angelman syndrome to the loci on human chromosome 15 [q11-13] is being used as a marker to highlight the complementary sequence in higher primates. We hybridized metaphase chromosomes of chimpanzee (PTR), gorilla (GGO), and orangutan (PPY) with this probe (Oncor) to characterize the chromosomal segments because the nature of these pericentric inversions remains relatively unknown. Our observations suggest that a pericentric inversion has occurred in chimpanzee chromosome (PTR 16) which corresponds to human chromosome 15 at PTR 16 band p11-12, while in gorilla (GGO 15) and orangutan (PPY 16) the bands q11-13 complemented to human chromosome 15 band q11-13. This approach has proven to be a better avenue to characterize the pericentric inversions which have apparently occurred during human evolution. "Genetic" divergence in the speciation process which occurs through "chromosomal" rearrangement needs to be reevaluated and further explored using newer techniques.
J Mol Evol 1995 Aug
PMID:The genomic sequence for Prader-Willi/Angelman syndromes' loci of human is apparently conserved in the great apes. 766 55

We have isolated a novel gene from the Prader-Willi syndrome (PWS) smallest region of deletion overlap in proximal human chromosome 15q. IPW (Imprinted gene in the Prader-Willi syndrome region) was isolated using the direct selection method and yeast artificial chromosomes localized to the deletion region. IPW is spliced and polyadenylated but its longest open reading frame codes for only 45 amino acids, suggesting that it functions as an RNA, similar to H19 and XIST. The RNA is widely expressed in adult and fetal tissues and is found in the cytoplasmic fraction of human cells, which is also the case for the H19 non-translated RNA, but differs from the XIST RNA which is found predominantly in the nucleus. Using a sequence polymorphism, exclusive expression from the paternal allele in lymphoblasts and fibroblasts was demonstrated; monoallelic expression was found in fetal tissues. IPW is located about 150 kb distal to SNRPN, the only other known gene in the deletion interval, and about 50 kb proximal to the breakpoint of a translocation which defines the distal end of the PWS region and the proximal end of the Angelman syndrome (AS) region. As is the case with SNRPN, PWS patients with 15q11-q13 deletions do not express IPW, whereas expression is normal in Angelman syndrome patients. Lack of expression of IPW may contribute to the PWS phenotype directly. Alternatively, the mRNA product of IPW may play a role in the imprinting process, acting either on genes located proximally in the PWS region or distally in the AS region.
Hum Mol Genet 1994 Oct
PMID:Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. 784 16

Angelman syndrome (AS) is a neurogenetic disorder arising from a lack of genetic contribution from the maternal chromosome 15q11-13. To date, the AS critical region has been defined by an inherited deletion of approximately 1.5Mb, spanning the 3-21 (D15S10), LS6-1 (D15S113) and GABRB3 loci. We have identified an individual with the typical features of AS who has a deletion of the maternal chromosome which encompasses LS6-1, but does not extend to either flanking marker. This deletion, initially detected by (CA)n repeat analysis, was further characterised by fluorescence in situ hybridisation (FISH) using cosmids derived from a 260 kb LS6-1 yeast artificial chromosome (YAC). Neither end cosmid from this YAC clone falls within the deletion, suggesting that the minimal AS region is less than 200 kb. We also studied three loci within 15q11-13 which detect parent-of-origin specific DNA methylation imprints, and found that both normal maternal and paternal patterns were present in this patient.
Hum Mol Genet 1994 Aug
PMID:Angelman syndrome associated with a maternal 15q11-13 deletion of less than 200 kb. 798 24

In order to identify genes in the Prader-Willi/Angelman syndrome critical region, radiolabeled cDNA probes from poly(A)+ RNA from mouse tissues were used to identify potential exon-containing genomic DNA fragments in cosmid or phage clones from appropriate yeast artificial chromosomes, and these fragments were subsequently used to screen human cDNA libraries. A mouse brain cDNA probe was effective in detecting control genes of various abundance including small nuclear ribonucleoprotein polypeptide N (SNRPN), hypoxanthine-guanine phosphoribosyl transferase, glyceraldehyde-3-phosphate dehydrogenase, and beta-actin. Two genes mapping within the Angelman syndrome critical region were isolated. One gene was found to encode the E6-associated protein (E6-AP; gene symbol HPVE6A), a protein which interacts with the E6 protein of human papilloma virus. The other gene is previously uncharacterized and is designated PAR-2 (D15S225E) for Prader-Willi and Angelman region-gene 2. Imprinting analysis using reverse transcription-polymerase chain reaction of RNA from fibroblasts and lymphoblasts of deletion Prader-Willi and Angelman patients demonstrated imprinting of SNRPN with exclusive expression from the paternal allele, but E6-AP and PAR-2 were not imprinted in these cultured human cells. The ability to analyze for imprinting and expression of SNRPN and other genes in this region in cultured human cells will be a valuable tool for analyzing the molecular basis of the Prader-Willi and Angelman syndromes, although imprinting may differ between cultured cells and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1994 Feb
PMID:Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). 800

The Prader-Willi syndrome and the Angelman syndrome are caused by the loss of function of distinct but closely linked genes on human chromosome 15. Based on a yeast artificial chromosome restriction map and two key patients we have determined that the shortest region of deletion overlap in the Prader-Willi syndrome comprises 320 kb. The region includes the anonymous DNA marker PW71 (D15S63) and the gene for the small nuclear ribonucleoprotein N (SNRPN). The SNRPN gene maps 130 kb distal to PW71 and is transcribed from centromere to telomere.
Hum Mol Genet 1993 Dec
PMID:Molecular definition of the Prader-Willi syndrome chromosome region and orientation of the SNRPN gene. 811 65

The majority of cases of the two distinct disorders Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from cytogenetic deletions of chromosome 15q11-q13. These deletions are exclusively of maternal origin in AS but of paternal origin in PWS indicating that the 15q11-q13 region is subject to genomic imprinting. Transmission of a submicroscopic deletion in one three generation family resulted in AS only upon maternal transmission of the deletion with no clinical phenotype associated with paternal transmission (1,2). The breakpoint of this submicroscopic deletion has been cloned and sequenced. This is the first deletion junction from the AS/PWS region which has been so characterized. The nucleotide sequence of the deletion junction revealed a 19 bp insertion of unknown origin with no evidence of repetitive elements. A probe from the proximal deletion breakpoint, PB11, lies within the currently defined minimum region of deletion overlap in PWS, which contains the SNRPN and D15S63 loci. Our results suggest that the imprinted gene(s) responsible for the PWS phenotype are proximal of pB11 in this deletion overlap region.
Hum Mol Genet 1993 Jul
PMID:Cloning of the breakpoints of a submicroscopic deletion in an Angelman syndrome patient. 836 75

We have established a probe order within the Angelman/Prader-Willi chromosomal regions by multicolor fluorescence in situ hybridization (FISH). The probe [locus] order extending distally from the centromere is 34[D15S9]-IR4-3R[D15S11]-189-1[D15S13]-PW71++ + [D15S63]-3-21[D15S10]-28 beta 3-H3[GABRB3]-IR10-1 [D15S12]. This order agrees with that recently reported (1) with the exception of PW71 [D15S63]. In addition, a second gamma-aminobutyric acid (GABAA) receptor, the alpha 5 subunit, has been localized within the reference map to between GABRB3 and D15S12. The locus order was further confirmed by DNA hybridization analysis of two patients, one with Angelman syndrome and one with Prader-Willi syndrome, with different unbalanced translocations and molecular extents of deletion. Our results provide a framework map of chromosome 15q11-q13 into which additional markers can be oriented and allow a further differentiation of the critical genetic regions of the two syndromes.
Hum Mol Genet 1993 Feb
PMID:FISH ordering of reference markers and of the gene for the alpha 5 subunit of the gamma-aminobutyric acid receptor (GABRA5) within the Angelman and Prader-Willi syndrome chromosomal regions. 838 64

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by a deficiency of paternal (PWS) or maternal (AS) contributions for chromosome 15 by either deletion or uniparental disomy (UPD). To further study the molecular mechanisms involved in these disorders and to improve molecular diagnostic methods, we have isolated three dinucleotide repeat markers in the PWS/AS critical region. An Alu-CA PCR method was used to isolate CA-repeat markers directly from yeast artificial chromosome (YAC) clones identified by probes IR4-3R (D15S11), LS6-1 (D15S113), and GABAA receptor B3 (GABRB3). Three markers with 6-11 alleles and 73-83% heterozygosities were identified and analyzed by multiplex PCR. Gene-centromere mapping was performed on a panel of ovarian teratomas of known meiotic origin, and showed the most proximal marker, IR4-3R, to be 13 cM (95% confidence limits: 7-19 cM) from the centromere of chromosome 15. Molecular diagnostic studies were performed on 20 PWS and 9 AS patients. In 17 patients with deletions, the parental origin of deletion was determined. Ten PWS patients were shown to have maternal heterodisomy. Since these markers are only 13 cM from the centromere, heterodisomy indicates that maternal meiosis I nondisjunction is involved in the origin of UPD. In contrast, two paternal disomy cases of AS showed isodisomy for all markers tested along the length of chromosome 15. This suggests a paternal meiosis II nondisjunction event (without crossing over) or, more likely, monosomic conception (due to maternal nondisjunction) followed by chromosome duplication.(ABSTRACT TRUNCATED AT 250 WORDS)
Hum Mol Genet 1993 Feb
PMID:Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy. 849 3


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