Human Genetics

, Volume 87, Issue 2, pp 112–118 | Cite as

Deletion of chromosome 21 and normal intelligence: molecular definition of the lesion

  • Julie R. Korenberg
  • Dagmar K. Kalousek
  • Goran Anneren
  • Stefan-M. Pulst
  • Judith G. Hall
  • Charles J. Epstein
  • David R. Cox
Original Investigations
Received:
Revised:

Summary

Application of a method for the fine structure analysis of unbalanced chromosomal rearrangements using quantitative Southern blot analysis has established that an individual of normal intelligence and largely normal appearance has a significant interstitial deletion of chromosome 21. Using high resolution cytogenetic analysis and molecular analysis with five single copy DNA sequences unique to chromosome 21 and a probe for human SOD1 (CuZn, Superoxide dismutase), we find that the deletion extends from the border of bands 21q11.1–11.2 and extends to the border of bands 21q21.2–q21.3. The latter border is established molecularly by the presence of two copies of SOD1, previously mapped to band 21q22.1, and of four single copy sequences known to be located distal to this region. The presence of SOD1 was confirmed by enzyme dosage analysis. These findings demonstrate that deletion of close to 20,000kb of autosomal material is compatible with normal intelligence. Further, they suggest that chromosome 21 may include a large region of relative developmental neutrality whose molecular basis may now be investigated. Because of the limits of even high resolution cytogenetic analysis, fine structure molecular analyses of this type will be necessary to reliably detect and define similar small chromosomal deletions or insertions. The molecular definition of such aneuploidy provides the basis for increasing the resolution of the human physical genetic map.

Keywords

CuZn Chromosomal Deletion Normal Intelligence Enzyme Dosage Interstitial Deletion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. Abeliovich D, Carmi R, Karplus M, Bar-Ziv J, Cohen MM (1979) Monosomy 21: a possible stepwise evolution of the karyotype. Med Genet 4:279–286Google Scholar
  2. Bernardi G, Olofsson B, Filipski J, Zerial M, Saunas J, Cuny G, Meunier Rotival M, Rodier F (1985) The mosaic genome of warm-blooded vertebrates. Science 228:953–958Google Scholar
  3. Couturier J, Morichon-Delvallez N, Dutrillaux B (1985) Deletion of band 13q21 is compatible with normal phenotype. Hum Genet 70:87–91Google Scholar
  4. Daniel A (1979) Normal phenotype and partial trisomy for the G positive region of chromosome 21. J Med Genet 16:227–235Google Scholar
  5. Epstein CJ (1986) Consequences of chromosome imbalance: principles, mechanisms, and models. Cambridge University Press, New YorkGoogle Scholar
  6. Fraser C, Eaves CJ, Kalousek DK (1987) Fluorodeoxyuridine synchronization of hemopoietic colonies. Cancer Genet Cytogenet 24:1–6CrossRefPubMedGoogle Scholar
  7. Fried R (1975) Enzymatic and non-enzymatic assay of superoxide dismutase. Biochemie 57:657–660Google Scholar
  8. Gardiner K, Horisberger M, Kraus J, Tantravahi U, Korenberg J, Rao V, Reddy S, Patterson D (1990) Analysis of human chromosome 21: correlation of physical and cytogenetic maps: gene and CpG island distribution. EMBO J 9:25–34Google Scholar
  9. Goldman MA, Holmquist GP, Gray MC, Caston LA, Nag A (1984) Replication timing of genes and middle repetitive sequences. Science 224:686–692Google Scholar
  10. Holmquist GP (1989) Evolution of chromosome bands: molecular ecology of noncoding DNA. J Mol Evol 28:469–486Google Scholar
  11. Korenberg JR, Engels WR (1978) Base ratio, DNA content, and quinacrine brightness of human chromosome. Proc Natl Acad Sci USA 75:3382–3386Google Scholar
  12. Korenberg JR, Rykowski MC (1988) Human genome organization: Alu, LINES, and the molecular structure of metaphase chromosome bands. Cell 53:391–400CrossRefPubMedGoogle Scholar
  13. Korenberg JR, Therman E, Denniston C (1978) Hot spots and functional organization of human chromosomes. Hum Genet 43:13–22Google Scholar
  14. Korenberg JR, Kalousek DK, Anneren KG, Hall JG, Epstein C, Cox DR (1986) Deletion of chromosome 21 and normal intelligence: molecular definition of the lesion. Am J Hum Genet 39:A119Google Scholar
  15. Korenberg JR, Croyle ML, Cox DR (1987) Isolation and regional mapping of DNA sequences unique to human chromosome 21. Am J Hum Genet 41:963–978Google Scholar
  16. Korenberg JR, Kawashima H, Pulst SM, Ikeuchi T, Ogasawara N, Yamamoto K, Schonberg A, West R, Allen L, Magenis E, Ikawa K, Taniguchi N, Epstein CJ (1990) Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet 47:236–246Google Scholar
  17. Korenberg JR, Pulst SM, Neve RL, West R (1989) The Alzheimer amyloid precursor protein maps to human chromosome 21 bands q21. 105-q21.05. Genomics 5:124–127Google Scholar
  18. Lowry DH, Rosenrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  19. Maniatis T, Fritsch EF, Sambrook J (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor NY, pp 280–281Google Scholar
  20. McCormick MK, Schinzel A, Petersen MB, Stetten G, Driscoll DJ, Cantu ES, Tranebjaerg L, Mikkelsen M, Watkins PC, Antonarakis SE (1989) Molecular genetic approach to the characterization of the “Down syndrome region” of chromosome 21. Genomics 5:325–332Google Scholar
  21. Nakamura Y, Leppert M, O'Connell P, Wolff R, Holm T, Culver M, Martin C, Fujimoto E, Hoff M, Kumlin E, White R (1987) Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 235:1616–1622Google Scholar
  22. Overhauser J, Golbus MS, Schonberg SA, Wasmuth JJ (1986) Molecular analysis of an unbalanced deletion of the short arm of chromosome 5 that produces no phenotype. Am J Hum Genet 39:1–10Google Scholar
  23. Pulst SM, Yang-Feng T, Korenberg JR (1991) Relative order and location of DNA sequences on chromosome 21 linked to familial Alzheimer disease. Am J Med Genet (in press)Google Scholar
  24. Reynolds JF, Wyandt HE, Kelly TE (1985) De novo interstitial deletion in a retarded boy with ulno-fibular dysostosis. Am J Med Genet 20:173–180Google Scholar
  25. Roland B, Cox DM, Hoar DI, Fowlow SB, Robertson AS (1990) A familial interstitial deletion of the long arm of chromosome 21. Clin Genet 37:423–428Google Scholar
  26. Salin ML, McCord JM (1974) Superoxide dismutase in polymorphonuclear leukocytes. J Clin Invest 54:1005–1009Google Scholar
  27. Schinzel A (1984) Catalogue of unbalanced chromosome aberrations in man. de Gruyter, Berlin New YorkGoogle Scholar
  28. Sinet PM, Couturier J, Dutrillaux B, Poissonnier M, Raqul O, Rethore MO, Allard D, Lejeune J, Jerome H (1976) Trisomie 21 et superoxyde dismutase-1 (IPO-A) tentative de localisation sur las sous bande 21q21. 1. Exp Cell Res 97:47–55Google Scholar
  29. Singer MF (1982) Highly repeated sequences in mammalian genomes. Int Rev Cytol 76:67–112Google Scholar
  30. Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517PubMedGoogle Scholar
  31. Warren RJ, Rimoin DL (1970) The G deletion syndromes. J Pediatr 77:658–663Google Scholar
  32. Weil J, Epstein CJ (1979) The effect of trisomy 21 on the patterns of polypeptide synthesis in human fibroblasts. Am J Hum Genet 31:478–488Google Scholar
  33. Yamamoto Y, Ogasawara N, Gotoh A, Komiya H, Nakai H, Kuroki Y (1979) A case of 21q-syndrome with normal SOD-1 activity. Hum Genet 48:321–327Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Julie R. Korenberg
    • 1
  • Dagmar K. Kalousek
    • 2
  • Goran Anneren
    • 3
  • Stefan-M. Pulst
    • 1
  • Judith G. Hall
    • 2
  • Charles J. Epstein
    • 4
  • David R. Cox
    • 5
  1. 1.Medical Genetics Birth Defects Center, ASB-3, Ahmanson Department of Pediatrics, Cedars-Sinai Medical CenterUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  3. 3.Department of Clinical GeneticsUniversity HospitalUppsalaSweden
  4. 4.Department of PediatricsUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of Psychiatry and Department of BiochemistryUniversity of CaliforniaSan FranciscoUSA

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