Hostname: page-component-7479d7b7d-rvbq7 Total loading time: 0 Render date: 2024-07-13T02:39:50.791Z Has data issue: false hasContentIssue false
  • English
  • Français

The Search for Molecular Defects in Genetic Disease

Published online by Cambridge University Press:  01 August 2014

H. Galjaard
H. Galjaard*
Affiliation:
Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands
*
Department of Clinical Genetics, Erasmus University Rotterdam- P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

Extract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

In most wealthy industrialized countries, socioeconomic circumstances, hygiene and medical care have improved to such an extent that perinatal complications and congenital disorders have become the major causes of infant mortality and of chronic handicap in children [1].

In the past four decades, we have made impressive advances understandig the cytogenetic and molecular basis of congenital disorders. Dozens of syndromes associated with multiple physical handicaps and mental retardation have been related to specific numerical or structural chromosome aberrations. In situ hybridization and the development of a rapidly increasing number of DNA probes enable the detection of chromosomal abnormalities with a resolution down to the level of a single gene. The discovery of tumor-associated chromosomal aberrations, microdeletions, more than a hundred oncogenes, and the cloning of tumor suppressor genes are illustrations of the importance of molecular cytogenetics.

When I started my scientific career at the end of the fifties, some 1,000 syndromes were proven or suspected to be subject to Mendelian inheritance and this number has now increased to more than 6,600 [2]. Progress in elucidating the protein defects responsible for these single gene disorders has been much slower and currently about 400 protein defects have been delineated [3]. This knowledge has been important not only for basic research on biochemical pathways and cell biology, but has also provided new perspectives for early laboratory diagnosis of index patients, carrier detection, genetic counseling and in some instances, such as phenylketonuria, for newborn screening and early treatment [4]. In those instances where a protein defect is also expressed in cultured skin fibroblasts, amniotic cells or chorionic villi, prenatal diagnosis becomes possible for couples at increased risk [5, 6].

Type
Research Article
Information
Acta geneticae medicae et gemellologiae: twin research , Volume 45 , Issue 1-2 , April 1996 , pp. 43 - 52
Copyright
Copyright © The International Society for Twin Studies 1996

References

REFERENCES

1. Galjaard, H: Genetic technology in health care: A global view. Int J Tech Assess 1994; 10, 4: 527–545.CrossRefGoogle Scholar
2. McKusick, VA: Mendelian Inheritance in Man, ed. 7. Baltimore, Johns Hopkins University Press, 1994.Google Scholar
3. Scriver, CR, Beaudet, AL, Sly, WS, Valle, D (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 7. New York, McGraw Hill, 1995.Google Scholar
4. Emery, AEH, Rimoin, DL (eds): Principles and Practice in Medical Genetics, ed 2. Edinburgh, Churchill Livingstone, 1991.Google Scholar
5. Drife, JO, Donnai, D (eds): Antenatal Diagnosis of Fetal Abnormalities. Berlin, Springer, 1991.CrossRefGoogle Scholar
6. Milunsky, A (ed): Genetic Disorders and the Fetus. Baltimore, Johns Hopkins University Press, 1992.Google Scholar
7. Kan, YW, Dozy, AM: Polymorphism of DNA sequence adjacent to human ß globin structural gene: Relationship to sickle mutation. Proc Natl Acad Sci USA 1978; 75: 5631–5635.CrossRefGoogle Scholar
8. Suzuki, Y, Sakubara, H, Oshima, A: ß-Galactosidase deficiency: GM 1-gangliosidosis and Morquio B disease; in Scriver CR, Beaudet Al, Sly Ws, Valle, D/ (eds): The Metabolic and Molecular Bases of Inherited Disease, ed. 7. New York, Mc Graw Hill, 1995, pp 2785–2824.Google Scholar
9. D'Azzo, A, Andria, G, Strisciuglio, P, Galjaard, H: Galactosialidosis; in Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 7. New York, McGraw Hill, 1995, pp 2825–2838.Google Scholar
10. D'Azzo, A, Hoogeveen, A, Reuser, AJ, Robinson, D, Galjaard, H: Molecular defect in combined ß-galactosidase and neuraminidase deficiency in man. Proc Natl Acad Sci USA 1982; 79: 4535–4539.CrossRefGoogle Scholar
11. Galjart, NJ, Morreau, H, Willemsen, R, Gillemans, N, Bonten, EJ, d'Azzo, A: Human lysosomal protective protein has cathepsin-A-like activity distinct for its protective function. J Biol Chem 1991; 266: 14754–14762.CrossRefGoogle ScholarPubMed
12. Desnick, RJ, Wang, AM; α-N-Acetylgalactosaminidase deficiency: Schindler disease; in Scriver, R, Beaudet, AL, Sly, WS, Valle, D, (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 7. New York, McGraw Hill, 1995, pp 2509–2528.Google Scholar
13. Van Diggelen, OP, Schindler, D, Kleijer, WJ, Huijmans, JMG, Galjaard, H, Linden, HU, Peter-Katalinic, J, Egge, H, Dabrowski, U, Cantz, M: Lysosomal α-N-acetylgalactosaminidase deficiency: A new inherited metabolic disease. Lancet 1987; ii: 804–805.CrossRefGoogle Scholar
14. Aula, PP, Autio, S, Raivio, KO, Rapola, J, Thoden, CJ, Koskela, SL, Yamashina, L: ‘Salla disease’: A new lysosomal storage disorder. Arch Neurol 1979; 36: 88–94.CrossRefGoogle ScholarPubMed
15. Renlund, M, Aula, PP, Raivio, KD, Autio, S, Sainio, K, Rapola, J, Koskela, SL: Salla disease: A new lysosomal storage disorder with distributed sialic acid metabolism. Neurology 1983; 33: 57–66.CrossRefGoogle Scholar
16. Gahl, WA, Schneider, JA, Aula, PP: Lysosomal transport disorders: Cystinosis and sialic acid storage disorders; in Scriver, CR, Beaduet, AL, Sly, WS, Valle, D, (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 7. New York, McGraw Hill, pp 3763–3798.Google Scholar
17. Mancini, GMS, De Jonge, HR, Galjaard, H, Verheijen, FW: Characterization of a proton-driven carrier for sialic acid in the lysosomal membrane: Evidence for a group specific transport system for acidic monosaccharides. J Biol Chem 1989; 264: 15247–15254.CrossRefGoogle ScholarPubMed
18. Mancini, GMS, Beerens, CEMT, Aula, PP, Verheijen, FW: Sialic acid storage diseases. J Clin Invest, 1991; 87: 105–111.Google ScholarPubMed
19. Mancini, GMS, Beerens, CEMT, Galjaard, H, Verheijen, FW: Functional reconstitution of the lysosomal sialic acid carrier into proteoliposomes. Proc Natl Acad Sci USA, 1992; 89: 6609–6613.CrossRefGoogle ScholarPubMed
20. Gusella, JF, Wexler, NS, Conneally, PM, Naylor, SL: A polymorphic DNA marker genetically linked to Huntington's disease. Nature 1983; 306: 234–238.CrossRefGoogle ScholarPubMed
21. The Huntington Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable in Huntington disease chromosomes. Cell 1993; 72: 971–983.CrossRefGoogle Scholar
22. Colling, FS: Positional cloning: Let's not call it reverse anymore. Nat Genet 1992; 1:3.CrossRefGoogle Scholar
23. Beaudet, AL, Scriver, CR Sly, WS, Valle, D: Genetics, biochemistry and molecular basis of variant human phenotypes; in Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, (eds): The Metabolic and Molecular Bases of Inherited Disease, ed 7. New York, McGraw Hill, 1995, pp 53–228.Google Scholar
24. Verkerk, AJMH, Pieretti, M, Sutcliffe, JS, Fu, Y, Kuhl, DP; Pizzuti, A, Reiner, O, Richards, S, Victoria, MF, Zhang, FP, Eussen, BE, Van Ommen, GJB, Blonden, LAJ, Riggens, GJ, Chastain, JL, Kunst, CB, Galjaard, H, Caskey, CT, Nelson, DL, Oostra, BA, Warren, ST: Identification of a gene (FMR-1) containing a CGG repeat coincident with a fragile X breakpoint cluster region exhibiting length variation in Fragile X syndrome. Cell 1991; 65: 905–914.CrossRefGoogle ScholarPubMed
25. Verheij, C, Bakker, CE, de Graaff, E, Keulemans, J, Willemsen, R, Verkerk, AJMH, Galjaard, H, Reuser, AJJ, Hoogeveen, AT, Oostra, BA: Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 1993; 363: 722–724.CrossRefGoogle ScholarPubMed
26. The Dutch-Belgian Fragile X Consortium: FMR-1 knockout mice: A model to study Fragile X mental retardation. Cell 1994;78: 23–33.Google Scholar
27. The European Chromosome 16 Tuberous Sclerosis Consortium: Identification and characterization of the tuberosis sclerosis gene on chromosome 16. Cell 1993; 75: 1305–1315.CrossRefGoogle Scholar
28. Wu, YQ, Heutink, P, de Vries, BA, Sandkuyl, LA, van den Ouweland, AMW, Niermeijer, MF, Galjaard, H, Reijniers, E, Willems, PJ, Halley, DJJ: Assignment of a second locus for multiple exostosis to the pericentromeric region of chromosome 11. Hum Mol Genet 1994; 3: 167–171.CrossRefGoogle Scholar
29. Heutink, P, vander Meij, AGL, Sandkuyl, LA, van Gils, APG, Bardoel, A, Breedveld, GJ, van Vliet, M, van Ommen, GJB, Cornelisse, CJ, Oostra, B, Weber, JL, Devilee, P: A gene subject to genomic imprinting and responsible for hereditary paragangliomas map to chromosome 11q23-qter. Hum Mol Genet 1992; 1:7–10.CrossRefGoogle Scholar
30. Heutink, P, Zguricas, J, van Oosterhout, L, Breedveld, GJ, Testers, L, Sandkuyl, LA, Snijders, PJLM, Weissenbach, J, Lindhout, D, Hovius, SER, Oostra, BA: The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nat Genet 1994; 6: 287–292.CrossRefGoogle Scholar
31. Hoogeveen, AT, Willemsen, R, Meijer, N, de Rooy, KE, Roos, RAC, van Ommen, GJB, Galjaard, H: Characterization and localization of the Huntington disease gene product. Hum Mol Genet 1993; 2: 2069–2073.CrossRefGoogle ScholarPubMed
32. The European Polycystic Kidney Disease Consortium: The polycystic kidney disease-1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 1994; 77: 881–894.CrossRefGoogle Scholar
33. Galjaard, H: Challenges for the future; in Emery, AEH, Rimoin, DL (eds): Principles and Practice of Medical Genetics, ed 2. Edinburgh, Churchill Livingstone, 1991, pp. 2025–2035.Google Scholar