Abstract
ICF syndrome (ICFS) is a rare immunodeficiency disorder characterized by instability of the pericentromeric heterochromatin predominantly of chromosomes 1 and 16. DNA methylation studies in two unrelated ICFS patients provide further evidence for a marked hypomethylation of satellite 2 DNA. The ICFS-specific disturbances of chromatin structure take place within the satellite 2 DNA regions, as demonstrated by fluorescence in situ hybridization analysis. Moreover, methylation studies of genomic imprinted loci D15S63, D15S9, and H19 have revealed hypomethylation to different degrees in both patients; this provides evidence for hypomethylation at autosomal single copy loci in ICFS. Cell fusion experiments have revealed a distinct reduction of chromosomal abnormalities in ICFS cells after fusion with normal cells, suggesting that the abnormalities are caused by the loss of function of an as yet unknown trans acting factor. Although it is now clear that wide-spread DNA hypomethylation is a characteristic feature of ICFS, neither the cause and mechanism of hypomethylation nor their relationship to the clinical symptoms is known. We speculate that a phenotypic effect might result from tissue-dependent abnormal gene expression and/or from a possible structural disturbance of DNA domains, which, with respect to the immunodeficiency, partially prevents the normal somatic recombinations in immunologically active cells.
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Bartsch O, Schwinger E (1991) A simplified protocol for fluorescence in situ hybridization with repetitive DNA probes and its use in clinical cytogenetics. Clin Genet 40:47–56
Bird A (1992) The essentials of DNA methylation. Cell 70:5–8
Boyd Y, Fraser NJ (1990) Methylation patterns at the hypervariable X-chromosome locus DXS255 (M27b); correlation with X-inactivation status. Genomics 7:182–187
Chen P, Imray FP, Kidson C (1984) Gene dosage and complementation analysis of ataxia telangiectasia lymphoblastoid cell lines assayed by induced chromosome aberration. Mutat Res 129:165–172
Cooke HJ, Hindley J (1979) Cloning of human satellite DNA: different components are on different chromosomes. Nuleic Acids Res 6:3177–3197
Deininger PL (1989) In: Howe M, Berg P (eds) Mobile DNA. ASM Press, Washington DC, pp 619–636
Dittrich B, Robinson WP, Knoblauch H, Buiting K, Schmidt K, Gillessen-Kaesbach G, Horsthemke B (1992) Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-oriain-specific DNA methylation in 15q11–13. Hum Genet 90:313–315
Dittrich B, Buiting K, Gro b S, Horsthemke B (1993) Characterization of a methylation imprint in the Prader-Willi syndrome chromosome region. Hum Mol Genet 2:1995–1999
Driscoll DJ, Waters MF, Williams CA, Zori RT, Glenn CC, Avidano KM, Nicholls RD (1992) A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics 13:917–924
Fasth A, Forestier E, Holmberg E, Holmgren G, Nordenson I, Söderström T, Wahlström J (1990) Fragility of the centromeric region of chromosome 1 associated with combined immunodeficiency in siblings. Acta Paediatr Scand 79:605–612
Frommer M, Prosser J, Tkachuk D, Reisner AH, Vincent PC (1982) Simple repeated sequences in human satellite DNA. Nucleic Acids Res 10:547–563
Giannoukakis N, Deal C, Kukuvitis A, Rouleau G (1994) Variability of IGF2 in blood, among human individuals, correlates with H19 expression. International Symposium on Genomic Imprinting, Nov. 20–22, Firenze, Abstr. SR4, p 55
Gimelli G, Varone P, Pezzolo A, Lerone M, Pistoia V (1993) ICF syndrome with variable expression in sibs. J Med Genet 30:429–432
Haas O (1990) Centromeric heterochromatin instability of chromosome 1, 9, and 16 in variable immunodeficiency syndrome: a virus-induced phenomenon? Hum Genet 85:244–246
Hulten M (1978) Selective somatic pairing and fragility at 1q12 in a boy with common variable immunodeficiency: a new syndrome. Clin Genet 14:294
Jeanpierre M, Turleau C, Aurias A, Prieur M, Ledeist F, Fischer A, Viegas-Pequignot (1993). An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum Mol Genet 2:731–735
Kieback P, Wendisch H, Lorenz P, Kinkel K (1992) ICF-Syndrom. Monatsschr Kinderheilkd 140:91–94
Kochanek S, Renz D, Doerfler W (1993) DNA methylation in the Alu sequences of diploid and haploid primary human cells. EMBO J 12:1141–1151
Kokalj-Vokac N, Almeida A, Viegas-Pequignot E, Jeanpierre M, Malfoy B, Dutrillaux B (1993) Specific induction of uncoiling and recombination by azacytidine in classical satellite-containing constitutive heterochromatin. Cytogenet Cell Genet 63:11–15
Korenberg J, Rybowski MC (1988) Human genome organization: Alu, Lines, and the molecular structure of metaphase chromosome bands. Cell 53:391–400
Laird PW, Jaenisch R (1994) DNA methylation and cancer. Hum Mol Genet 3:1487–1495
Maraschio P, Zuffardi O, Dalla Fior T, Tiepolo L (1988) Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. J Med Genet 25:173–180
Meitinger T, Boyd Y, Anand R, Craig IW (1988) Mapping of Xp21 translocation breakpoints in and around the DMD gene by pulsed field electrophoresis. Genomics 8:315–322
Miniou P, Jeanpierre M, Blanquet V, Sibella V, Bonneau D, Herbelin C, Fischer A, Niveleau A, Viegas-Pequignot E (1994). Abnormal methylation pattern in constitutive and facultative (X inactive chromosome) heterochromatin of ICF patients. Hum Mol Genet 3:2093–2102
Moyzis RK, Albright KL, Bartholdi MF, Cram LS, Deaven LL, Hildebrand CE, Joste NE, Longmire JL, Meyne J, Schwarzacher-Robinson T (1987) Human chromosome-specific repetitive DNA sequences: novel markers for genetic analysis. Chromosoma 95:375–386
Miller OJ, Schnedl W, Allen J, Erlanger BF (1974) 5-Methylcytosine loclized in mammalian constitutive heterochromatin. Nature 251:636–637
Nicholls RD (1993) Genomic imprinting and uniparetnal disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet 46:16–25
Okada N (1991) Sines: short interspersed repeated elements of the eukaryotic genome. Curr Opin Genet Dev 1:498–504
Peterson CL (1994) The SMC family: novel motor proteins for chromosome condensation. Cell 79:389–392
Razin A, Cedar H (1991) DNA methylation and gene expression. Microbiol Rev 55:451–458
Sasaki H, Allen ND, Surani MA (1993) DNA methylation and genomic imprinting in mammals. In: Jost JP, Saluz HP (eds) DNA methylation: molecular biology and biological significance. Birkhäuser, Basel, pp 469–486
Schmid M, Haaf T, Grunert D (1984) 5-Azacytidine-induced undercondensations in human chromosomes. Hum Genet 67:257–263
Smeets DFC, Moog U, Weemaes CMR, Vaes-Peeters G, Merkx GFM, Niehof JP, Hamers G (1994) ICF syndrome: a new case and review of the literature. Hum Genet 94:240–246
Sutter D, Doerfler W (1980) Methylation of integrated adenovirus type 12 DNA sequences in transformed cells is inversely correlated with viral gene expession. Proc Natl Acad Sci USA 77:253–256
Taggaro J, Fernández-Peralta AM, Gonzáles-Aguilera JJ (1994) Chromosomal localisation of human satellites 2 and 3 by a FISH method using oligonucleotides as probes. Hum Genet 93:383–388
Tonegawa S (1983) Somatic generation of antibody diversity. Nature 302:575
Turleau C, Cabanis M-O, Girault D, Ledeist F, Mettey R, Puissant H, Prieur M, Grouchy J de (1989) Multibranched chromosomes in the ICF syndrome: immunodeficiency, centromeric instability, and facial anomalies. Am J Med Genet 32:420–424
Viegas-Péquignot E, Dutrilleaux B (1976) Segmentation of human chromosomes induced by 5-ACR (5-azacytidine). Hum Genet 34:247–254
Wegner R-D, Schulzke I, Haferburg J (1989) Improvement of chorionic villi analysis by a BrdU-banding technique. In: Antsakalis A, Metaxotou C (eds) Chorionic villi sampling and early prenatal diagnosis. Beta Medical Art, Athens, pp 196–202
Zhang Y, Tycko B (1992) Monoallelic expression of the human H19 gene. Nature Genet 1:40–44
Zhang Y, Shields T, Crenshaw T, Hao Y, Moulton T, Tycko B (1993) Imprinting of human H19: allele specific CpG methylation. Loss of the active allele in Wilms tumor, and potential for somatic allele switching. Am J Hum Genet 53:113–124
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Schuffenhauer, S., Bartsch, O., Stumm, M. et al. DNA, FISH and complementation studies in ICF syndrome: DNA hypomethylation of repetitive and single copy loci and evidence for a trans acting factor. Hum Genet 96, 562–571 (1995). https://doi.org/10.1007/BF00197412
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DOI: https://doi.org/10.1007/BF00197412