Abstract
The predominant genetic defects in Prader-Willi syndrome (PWS) are 15q11–q13 deletions of paternal origin and maternal chromosome 15 uni-parental disomy (UPD)1,2. In contrast, maternal deletions and paternal chromosome 15 UPD are associated with a different neurogenetic disorder, Angelman syndrome (AS)2,3. In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q11–q13 loci4. The critical PWS region has been narrowed to a ∼320-kb region between D15S63 and D15S1745 , encoding several imprinted transcripts, including PAR5, IPW, PAR1 (refs 7, 8) and SNRPN, which has so far been considered a strong candidate for the PWS gene6. A few PWS-associated microdeletions involving a putative imprinting centre (IC) proximal to SNRPN have also been observed7,9. We have mapped the breakpoint of a balanced translocation (9;15)pat associated with most of the PWS features between SNRPN and IPW/PAR1. Methylation and expression studies indicate that the paternal SNRPN allele is unaffected by the translocation, while IPW and PAR1 are unexpressed. This focuses the attention on genes distal to the breakpoint as the main candidate for PWS genes, and is consistent with a cis action of the putative 1C, and suggests that further studies of translocational disruption of the imprinted region may establish genotype/phenotype relationships in this presumptive contiguous gene syndrome.
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References
Ledbetter, D.H. et al. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. New Engl. J. Med. 304, 325–329 (1981).
Nicholls, R.D. Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am. J. Med. Genet. 46, 16–25 (1993).
Knoll, J.H.M. & Nicholls, R.D. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am. J. Med. Genet. 32, 285–290 (1989).
Dittrich, B. et al. Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific methylation in 15q11–13. Hum. Genet. 90, 313–315 (1992).
Buiting, K. et al. Molecular definition of the Prader-Willi syndrome chromosome region and orientation of the SNRPN gene. Hum. Molec. Genet. 2, 1991–1994 (1993).
Nakao, M. et al. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein and PAR-2 (D15S225E). Hum. Mol. Genet. 3, 309–315 (1994).
Sutcliffe, J.S. et al. Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8, 52–58 (1994).
Wewrick, R., Kerns, J.A. & Francke, U. Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum. Mol. Genet. 10, 1877–1882 (1994).
Buiting, K. et al. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nature Genet. 9, 395–400 (1995).
Prader, A., Labhart, A. & Willi, H., Syndrom von Adipositas,Kleinwuchs, Kryptorchismus und Oligophrenie nach myotonieartigem Zustand im Neugeborenenalter. Schweiz. med. Wochenschr. 86, 1260–1261 (1956).
Holm, V.A. et al. Prader Willi syndrome: consensus diagnostic criteria. Pediatrics 91, 398–401 (1993).
Mikkelsen, M., Poulsen, H., Grinsted, J. & Lange, A. Non-disjunction in trisomy 21: study of chromosomal heteromorphisms in 110 families. Ann. Hum. Genet. 44, 17–28 (1980).
Mutirangura, A. et al. A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11–q13) and refined localization of the SNRPN gene. Genomics 18, 546–552 (1993).
Kuwano, A. et al. Molecular dissection of the Prader-Willi/Angelman syndrome region (15q11–13) by YAC cloning and FISH analysis. Hum. Mol. Genet. 1, 417–425 (1992).
Dittrich, B., Suiting, K., Gross, S. & Horsthemke, B. Characterization of a methylation imprint in the Prader-Willi syndrome chromosome region. Hum. Mol. Genet. 2, 1995–1999 (1993).
Tommerup, N. Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders. J. Med. Genet. 30, 713–727 (1993).
Tommerup, N. & Vissing, H. Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders. Genomics. 27, 259–264 (1995).
Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).
Liang, P. et al. Differential display using one-base anchored oligo-dT primers. NucL Acids Res. 22, 5763–5764 (1994).
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Schulze, A., Hansen, C., Skakkebæk, N. et al. Exclusion of SNRPN as a major determinant of Prader-Willi syndrome by a translocation breakpoint. Nat Genet 12, 452–454 (1996). https://doi.org/10.1038/ng0496-452
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DOI: https://doi.org/10.1038/ng0496-452
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