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. 2003 Mar;72(3):571-7.
doi: 10.1086/367926. Epub 2003 Jan 23.

Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect

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Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect

Karin Buiting et al. Am J Hum Genet. 2003 Mar.

Abstract

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurogenetic disorders that are caused by the loss of function of imprinted genes in 15q11-q13. In a small group of patients, the disease is due to aberrant imprinting and gene silencing. Here, we describe the molecular analysis of 51 patients with PWS and 85 patients with AS who have such a defect. Seven patients with PWS (14%) and eight patients with AS (9%) were found to have an imprinting center (IC) deletion. Sequence analysis of 32 patients with PWS and no IC deletion and 66 patients with AS and no IC deletion did not reveal any point mutation in the critical IC elements. The presence of a faint methylated band in 27% of patients with AS and no IC deletion suggests that these patients are mosaic for an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited from either the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother. These data suggest that this imprinting defect results from a failure to erase the maternal imprint during spermatogenesis.

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Figures

Figure  1
Figure 1
Mosaic methylation defect. A, (MS)-PCR analysis of SNURF-SNRPN exon 1 in two patients with AS and an imprinting defect. Patient ASID-56 shows a typical AS methylation pattern, whereas patient ASID-55 has a faint methylated band. A faint methylated band (arrow) is also detected by MS Southern blot analysis. B, meth = methylated; unmeth = unmethylated; F = father; M = mother; B = BamHI; H = HpaII; M = MspI. In contrast to HpaII, MspI is not MS.
Figure  2
Figure 2
Methylation analysis of sperm DNA samples at D15S63 (PW71) and the AS-SRO A, Methylation analysis in different sperm samples with probe PW71 on DNA digested with HindIII + HpaII (top). In all sperm samples a methylated and an unmethylated band is present. Results are shown for methylation analysis in two sperm samples heterozygous for an NciI restriction site polymorphism (NciI*) at the D15S63 locus (middle). The different possible fragments for the methylated and unmethylated allele I and allele II are shown in the map below (not drawn to scale). The Southern blot (middle) shows the presence of a methylated and an unmethylated fragment for both alleles. B, Sequence analysis of two sperm DNA samples heterozygous for one or two SNPs inside the AS-SRO. Both sperm DNA samples were digested with HpaII and amplified with primers flanking the HpaII site. If methylation at this locus is allele specific, only the methylated allele should be amplified. By cloning the PCR products from sperm sample 1096, we obtained 11 clones from one allele and 14 from the other. For sperm sample 16, we obtained 11 clones from one allele and 12 clones from the other.

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References

Electronic-Database Information

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for PWS-SRO [accession number AC009696] and AS-SRO [accession number AF148319])
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for AS [MIM 105830] and PWS [MIM 176270])

References

    1. Buiting K, Barnicoat A, Lich C, Pembrey M, Malcolm S, Horsthemke B (2001) Disruption of the bipartite imprinting center in a family with Angelman syndrome. Am J Hum Genet 68:1290–1294 - PMC - PubMed
    1. Buiting K, Dittrich B, Groß S, Lich C, Färber C, Buchholz T, Smith E, et al (1998) Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170–180 - PMC - PubMed
    1. Buiting K, Färber C, Kroisel P, Wagner K, Brueton L, Robertson ME, Lich C, Horsthemke B (2000) Imprinting centre deletions in two PWS families: implications for diagnostic testing and genetic counseling. Clin Genet 58:284–290 - PubMed
    1. Buiting K, Lich C, Cottrell S, Barnicoat A, Horsthemke B (1999) A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum Genet 105:665–666 - PubMed
    1. Buiting K, Saitoh S, Groß S, Dittrich B, Schwartz S, Nicholls R, Horsthemke B (1995) Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting center on human chromosome 15. Nat Genet 9:395–400 - PubMed

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