Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 May;68(5):1290-4.
doi: 10.1086/320120. Epub 2001 Mar 23.

Disruption of the bipartite imprinting center in a family with Angelman syndrome

Affiliations

Disruption of the bipartite imprinting center in a family with Angelman syndrome

K Buiting et al. Am J Hum Genet. 2001 May.

Abstract

Imprinting in 15q11-q13 is controlled by a bipartite imprinting center (IC), which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome (PWS). Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome (AS). So far, in all affected sibs with an imprinting defect, an inherited IC deletion was identified. We report on two sibs with AS who do not have an IC deletion but instead have a 1-1.5 Mb inversion separating the two IC elements. The inversion is transmitted silently through the male germline but impairs maternal imprinting after transmission through the female germline. Our findings suggest that the close proximity and/or the correct orientation of the two IC elements are/is necessary for the establishment of a maternal imprint.

PubMed Disclaimer

Figures

Figure  1
Figure 1
A, IC region. The AS-SRO and the PWS-SRO are indicated by gray boxes. Blackened boxes indicate the SNRPN upstream exons u4 and u5. The inversion breakpoint inside the IC region is indicated by an arrow. B, Southern blot analysis of EcoRI-, SacI-, and XbaI-digested DNA from patient AW and from a normal control with probe AS-SROu+t (left) and probe L48.3Ip1p2 (right). The abnormal EcoRI fragment, detected with probe AS-SROu+t, which was subcloned, is indicated by an arrow. C, Partial sequences of the inversion breakpoints. The breakpoint junction fragment contains a 21-bp insertion of unknown origin.
Figure  2
Figure 2
Chromosomal region 15q11-q13. The extent of the common large deletions in patients with PWS and with AS are shown at the top of the figure. In class I deletions, the proximal breakpoint lies inside BP1. In class II deletions, the breakpoint lies inside BP2. The normal gene order in 15q11-q13 is given in the middle of the figure. The inversion is shown at the bottom.
Figure  3
Figure 3
A, Inversion-specific PCR in family AS-W. A 508-bp PCR product, specific for the inversion, was observed in the grandfather, his twin sib, the mother, and both affected sibs. Primer sequences for this PCR are: 5′ CAGCAT-GTAGCATGTATCTTTCTCA 3′ (Weju3) and 5′ CAGTATCCATTAGGG-ATTTGCAG3′ (Weju4). B, Expression analysis. DNase I–treated RNA, extracted from lymphoblastoid cells of the mother (II-1), was positive for MKRN3, as was RNA from a normal control. The integrity of the RNA samples was shown by amplification of a 496-bp transcript fragment from the β-actin locus. The RT-PCR primers are as follows: DD29 and RN153 for MKRN3 (Jong et al. 1999) and for β-actin, β-actin–F, and β-actin–R (F = 5′-TTGCTAT-CCAGGCTGTGCTATCCC-3′, R = 5′-AGCACTGTGTTGGCGTAC-AG-3′). +RT = RT-PCR with reverse transcriptase; −RT = RT-PCR without reverse transcriptase; H2O = RT-PCR without RNA.

Similar articles

Cited by

References

Electronic-Database Information

    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for PWS [MIM 176270] and AS [MIM 105830])

References

    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
    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, Lich C, Cottrell S, Barnicoat A, Horsthemke B (1999a) 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, Groß S, Ji Y, Senger G, Nicholls RD, Horsthemke B (1999b) Expressed copies of the MN7 (D15F37) gene family map close to the common deletion breakpoints in the Prader-Willi/Angelman syndromes. Cytogenet Cell Genet 81:247–253 - PubMed
    1. Buiting K, Färber C, Kroisel P, Wagner K, Brueton L, Robertson ME, Lich C, Horsthemke B (2000) Imprinting centre (IC) deletions in two PWS families: implications and strategies for diagnostic testing and genetic counselling. Clin Genet 58:284–290 - PubMed

Publication types