Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome

被引：228

作者：

Sparago, A

Cerrato, F

Vernucci, M

Ferrero, GB

Silengo, MC

Riccio, A

机构：

[1] Univ Naples 2, Dipartimento Sci Ambientali, I-81100 Caserta, Italy

[2] Univ Turin, Dipartimento Sci Pediat & Adolescenza, I-10126 Turin, Italy

来源：

NATURE GENETICS | 2004年 / 36卷 / 09期

关键词：

D O I：

10.1038/ng1410

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.

引用

收藏

页码：958 / 960

页数：3

相关论文

共 15 条

[1] Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene [J].

Bell, AC ;

Felsenfeld, G .

NATURE, 2000, 405 (6785) :482-485

[2] INHERITED MICRODELETIONS IN THE ANGELMAN AND PRADER-WILLI SYNDROMES DEFINE AN IMPRINTING CENTER ON HUMAN-CHROMOSOME-15 [J].

BUITING, K ;

SAITOH, S ;

GROSS, S ;

DITTRICH, B ;

SCHWARTZ, S ;

NICHOLLS, RD ;

HORSTHEMKE, B .

NATURE GENETICS, 1995, 9 (04) :395-400

[3] Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes [J].

Eggenschwiler, J ;

Ludwig, T ;

Fisher, P ;

Leighton, PA ;

Tilghman, SM ;

Efstratiadis, A .

GENES & DEVELOPMENT, 1997, 11 (23) :3128-3142

[4] DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms [J].

Feinberg, AP ;

Cui, HM ;

Ohlsson, R .

SEMINARS IN CANCER BIOLOGY, 2002, 12 (05) :389-398

[5] Methylation sequencing analysis refines the region of H19 epimutation in Wilms tumor [J].

Frevel, MAE ;

Sowerby, SJ ;

Petersen, GB ;

Reeve, AE .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (41) :29331-29340

[6] CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus [J].

Hark, AT ;

Schoenherr, CJ ;

Katz, DJ ;

Ingram, RS ;

Levorse, JM ;

Tilghman, SM .

NATURE, 2000, 405 (6785) :486-489

[7] Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive [J].

Kanduri, C ;

Pant, V ;

Loukinov, D ;

Pugacheva, E ;

Qi, CF ;

Wolffe, A ;

Ohlsson, R ;

Lobanenkov, VV .

CURRENT BIOLOGY, 2000, 10 (14) :853-856

[8] Beckwith-Wiedemann syndrome: imprinting in clusters revisited [J].

Maher, ER ;

Reik, W .

JOURNAL OF CLINICAL INVESTIGATION, 2000, 105 (03) :247-252

[9] The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains [J].

Pant, V ;

Mariano, P ;

Kanduri, C ;

Mattsson, A ;

Lobanenkov, V ;

Heuchel, R ;

Ohlsson, R .

GENES & DEVELOPMENT, 2003, 17 (05) :586-590

[10] CTCF maintains differential methylation at the Igf2/H19 locus [J].

Schoenherr, CJ ;

Levorse, JM ;

Tilghman, SM .

NATURE GENETICS, 2003, 33 (01) :66-69