Hostname: page-component-7479d7b7d-c9gpj Total loading time: 0 Render date: 2024-07-13T02:41:56.422Z Has data issue: false hasContentIssue false
  • English
  • Français

Fragile X Syndrome in Humans and Mice

Published online by Cambridge University Press:  01 August 2014

B. A. Oostra
B. A. Oostra*
Affiliation:
Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands
*
Department of Clinical Genetics, Erasmus University, P.O. Box 1738-3000 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.

Fragile X syndrome is the most common cause of interited mental retardation in humans, with a frequency of approximately 1 in 1200 males and 1 in 2500 females [1]. It is second only to Down syndrome as a genetic cause of mental retardation, which has an overall frequency of 1 in 600. These frequency estimates suggest that fragile X syndrome accounts for approximately 3% of mental retardation in males, and perhaps as much as 20% in males with IQs between 30 and 55 [2]. The disease derives its name from the observation of a fragile site at Xq27.3 in cultured lymphocytes, fibroblasts and amniocytes [3].

The phenotype of the fragile X syndrome is mental retardation, usually with an IQ in the 4-70 range [4] and a number of dysmorphic features: long face, everted ears and large testicles [for review see ref. 5] (Fig. 1). Not every patient shows all the physical symptoms, which are generally more apparent after childhood. Macroorchidism is a common feature of fragile X syndrome in more than 90% of postpuberal males. Some patients show hyperactivity and attention deficits as well as avoidance behaviour similar to autism. Affected females generally have a less severe clinical presentation, and their IQ scores are generally higher, with typically borderline IQs or mild mental retardation.

No gross pathological abnormalities have been described in the brains of fragile X patients. Only a few post-mortem brain studies of fragile X males have been described and the information is very limited, presenting only non-specific findings such as brain atrophy, ventricular dilatation and pyramidal neurons with abnormal dendritic spines. It has been shown that the volume of the hippocampus was enlarged compared to controls [6], while a significantly decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle was found [7]. Using magnetic resonance imaging it was shown that fragile X patients have an increased volume of the caudate nucleus [8]. The caudate volume is correlated with IQ and methylation status of the FMR1 gene.

Type
Research Article
Information
Acta geneticae medicae et gemellologiae: twin research , Volume 45 , Issue 1-2 , April 1996 , pp. 93 - 108
Copyright
Copyright © The International Society for Twin Studies 1996

References

REFERENCES

1. Webb, TP, Bundey, SE, Thake, AI, Todd, J: Population incidence and segregation ratios in the Martin-Bell syndrome. Am J Med Genet 1986; 23: 573–580.Google Scholar
2. Turner, G, Daniel, A, Frost, M: X-linked mental retardation, macro-orchidism, and the Xq27 fragile site. J Pediatr 1980; 96: 837–841.CrossRefGoogle ScholarPubMed
3. Sutherland, GR: Fragile sites on human chromosomes: Demonstration of their dependence on the type of tissue culture medium. Science 1977; 197: 265–266.Google Scholar
4. Fish, G, Arinami, T, Froster-Iskenius, U, Fryns, JP, Curfs, LM, Borggreaf, M, Howard-Peebles, PN, Schwartz, CE, Simensen, RJ, Shapiro, LR: Relationship between age and IQ among fragile X males: A multicenter study. Am J Med Genet 1991; 38: 481–487.Google Scholar
5. Hagerman, RJ: Physical and behavioral phenotype; in Hagerman, RJ, Silverman, AC (eds): Fragile X Syndrome: Diagnosis, Treatment and Research. Baltimore, John Hopkins University Press, 1991, pp 1–68.Google Scholar
6. Reiss, AL, Lee, J, Freund, L: Neuroanatomy of fragile X syndrome: The temporal lobe. Neurology 1994; 44: 1317–1324.Google Scholar
7. Reiss, AL, Aylwarth, E, Freund, LS, Joshi, PK, Bryan, RN: Neuroanatomy of fragile X syndrome: The posterior fossa. Ann Neurol 1991; 29: 26–32.Google Scholar
8. Reiss, AL, Abrams, MT, Greenlaw, R, Freund, L, Denckla, MB: Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat Med 1995; 1: 159–167.CrossRefGoogle ScholarPubMed
9. Verkerk, AJ, Pieretti, M, Sutcliffe, JS, Fu, YH, Kuhl, DP, Pizzuti, A, Reiner, O, Richards, S, Victoria, MF, Zhang, FP, Eussen, BE, Van Ommen, GJB, Blonden, LAJ, Riggins, 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 breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65: 905–914.CrossRefGoogle ScholarPubMed
10. Verkerk, AJ, Eussen, BH, Van Hemel, JO, Oostra, BA: Limited size of the fragile X site shown by fluorescence in situ hybridization. Am J Med Genet 1992; 43: 187–191.Google Scholar
11. Eichler, EE, Richards, S, Gibbs, RA, Nelson, DL: Fine structure of the human FMR1 gene. Hum Mol Genet 1993; 2: 1147–1153.Google Scholar
12. Bell, MV, Hirst, MC, Nakahori, Y, MacKinnon, RN, Roche, A, Flint, TJ, Jacobs, PA, Tommerup, N, Tranebjaerg, L, Froster-Iskenius, U, Kerr, B, Turner, G, Lindebaum, D, Winter, R, Pembrey, M, Thibodeau, S, Davies, KE: Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome. Cell 1991; 64: 861–866.Google Scholar
13. Vincent, A, Heitz, D, Petit, C, Kretz, C, Oberle, I, Mandel, JL: Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis. Nature 1991; 349: 624–626.Google Scholar
14. Oberlé, I, Rousseau, F, Heitz, D, Kretz, C, Devys, D, Hanauer, A, Boue, J, Bertheas, MF, Mandel, JL: Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 1991; 252: 1097–1102.CrossRefGoogle ScholarPubMed
15. Yu, S, Pritchard, M, Kremer, E, Lynch, M, Nancarrow, J, Baker, E, Holman, K, Mulley, JC, Warren, ST, Schlessinger, D, Sutherland, GR, Richards, RI: Fragile X genotype characterized by an unstable region of DNA. Science 1991; 252: 1179–1181.Google Scholar
16. Rousseau, F, Heitz, D, Tarleton, J, Macpherson, J, Malmgren, H, Dahl, N, Barnicoat, A, Mathew, C, Mornet, E, Tejada, I, Maddalena, A, Spiegel, R, Schinzel, A, Marcos, J, Schorderet, DF, Schaap, T, Maccioni, L, Russo, S, Jacobs, PA, Schwartz, C, Mandel, JL: A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB 12.3: The first 2,253 cases. Am J Hum Genet 1994; 55: 225–237.Google Scholar
17. Fu, YH, Kuhl, DP, Pizzuti, A, Pieretti, M, Sutcliffe, JS, Richards, S, Verkerk, AJ, Holden, JJ Fenwick, R Jr, Warren, ST, Oostra, BA, Nelson, DL, Caskey, CT: Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell 1991; 67: 1047–1058.Google Scholar
18. Hansen, RS, Gartier, SM, Scott, CR, Chen, SH, Laird, CD: Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum Mol Genet 1992; 1: 571–578.CrossRefGoogle ScholarPubMed
19. Homstra, IK, Nelson, DL, Warren, ST, Yang, TP: High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome. Hum Mol Genet 1993; 2: 1659–1665.Google Scholar
20. Pieretti, M, Zhang, FP, Fu, YH, Warren, ST, Oostra, BA, Caskey, CT, Nelson, DL: Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 1991; 66: 817–822.CrossRefGoogle ScholarPubMed
21. Sutcliffe, JS, Nelson, DL, Zhang, F, Pieretti, M, Caskey, CT, Saxe, D, Warren, ST: DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1992; 1: 397–400.CrossRefGoogle ScholarPubMed
22. Verheij, C, Bakker, CE, de Graaff, E, Keulemans, J, Willemsen, R, Verkerk, AJ, Galjaard, H, Reuser, AJ, Hoogeveen, AT, Oostra, BA: Characterization and localization of the FMR-1 gene product associated with fragile X syndrome. Nature 1993; 363: 722–724.Google Scholar
23. Devys, D, Lutz, Y, Rouyer, N, Bellocq, JP, Mandel, JL: The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet 1993; 4: 335–340.CrossRefGoogle ScholarPubMed
24. Rousseau, F, Heitz, D, Biancalana, V, Blumenfeld, S, Kretz, C, Boue, J, Tommerup, N, Van Der Hagen, C, DeLozier-Blanchet, C, Croquette, MF, Gilgenkranz, S, Jalbert, P, Voelckel, MA, Oberle, I, Mandel, JL: Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 1991; 325: 1673–1681.Google Scholar
25. Sutherland, GR, Gedeon, A, Komman, L, Donnelly, A, Byard, RW, Mulley, JC, Kremer, E, Lynch, M, Pritchard, M, Yu, S, Richards, RI: Prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence. N Engl J Med 1991; 325: 1720–1722.Google Scholar
26. Verkerk, AJ, de Vries, BB, Niermeijer, MF, Fu, YH, Nelson, DL, Warren, ST, Majoor-Krakauer, DF, Halley, DJ, Oostra, BA: Intragenic probe used for diagnostics in fragile X families. Am J Med Genet 1992; 43: 192–196.Google Scholar
27. Oostra, BA, Jacky, PB, Brown, WT, Rousseau, F: Guidelines for the diagnosis of fragile X syndrome: National Fragile X Foundation. J Med Genet 1993; 30: 410–413.Google Scholar
28. Rousseau, F, Robb, LJ, Rouillard, P, Derkaloustian, VM: No mental retardation in a man with 40% abnormal methylation at the FMR-1 locus and transmission of sperm cell mutations as premutations. Hum Mol Genet 1994; 3: 927–930.Google Scholar
29. McConkie-Rosell, A, Lachiewicz, A, Spiridigliozzi, GA, Tarleton, J, Schoenwald, S, Phelan, MC, Goonewardena, P, Ding, X, Brown, WT: Evidence that methylation of the FMR1 locus is responsible for variant phenotypic expression of the fragile X syndrome. Am J Hum Genet 1993; 53: 800–809.Google Scholar
30. Hagerman, RJ, Hull, CE, Safanda, JF, Carpenter, I, Staley, LW, Oconnor, RA, Seydel, C, Mazzocco, M, Snow, K, Thibodeau, SN, Kuhl, D, Nelson, DL, Caskey, CT, Taylor AK: High functioning fragile X males: Demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet 1994; 51: 298–308.Google Scholar
31. Brown, WT, Houck, GE, Jeziorowska, A, Levinson, FN, Ding, X, Dobkin, C, Zhong, N, Henderson, J, Brooks, SS, Jenkins, EC: Rapid, fragile-X carrier screening and prenatal diagnosis using a nonradioactive PCR test. JAMA 1993; 270: 1569–1575.Google Scholar
32. Verkerk, AJ, De Graaff, E, De Boulle, K, Eichler, EE, Konecki, DS, Reyniers, E, Manca, A, Poustka, A, Willems, PJ, Nelson, DL, Oostra, BA: Alternative splicing in the fragile X gene FMR1 . Hum Mol Genet 1993; 2: 399–404.CrossRefGoogle ScholarPubMed
33. Ashley, CT, Sutcliffe, JS, Kunst, CB, Leiner, HA, Eichler, EE, Nelson, DL, Warren, ST: Human and murine FMR-1: Alternative splicing and translational initiation downstream of the CGG-repeat. Nat Genet 1993; 4: 244–251.Google Scholar
34. Abitbol, M, Menini, C, Delezoide, AL, Rhyner, T, Vekemans, M, Mallet, J: Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain. Nat Genet 1993; 4: 147–153.Google Scholar
35. Bachner, D, Steinbach, P, Wohrle, D, Just, W, Vogel, W, Hameister, H, Manca, A, Poustka, A: Enhanced Fmr-1 expression in testis. Nat Genet 1993; 4: 115–116.Google Scholar
36. De Graaff, E, Willemsen, R, Zhong, N, De Die-Smulders, CEM, Brown, WT, Freiing, G, Oostra, BA: Instability of the CGG repeat and expression of the FMR1 protein in a male fragile X patient with a lung tumour. Am J Hum Genet, in press.Google Scholar
37. Gedeon, AK, Baker, E, Robinson, H, Partington, MW, Gross, B, Manca, A, Kom, B, Poustka, A, Yu, S, Sutherland, GR, Mulley, JC: Fragile X syndrome without CCG amplification has an FMR1 deletion. Nat Genet 1992; 1: 341–344.CrossRefGoogle ScholarPubMed
38. Wohrle, D, Kotzot, D, Hirst, MC, Manca, A, Kom, B, Schmidt, A, Barbi, G, Rott, HD, Poustka, A, Davies, KE, Steinbach, P: A microdeletion of less than 250 kb, including the proximal part of the FMR-1 gene and the fragile-X site, in a male with the clinical phenotype of fragile-X syndrome. Am J Hum Genet 1992; 51: 299–306.Google Scholar
39. Meijer, H, Degraaff, E, Merckx, D, Jongbloed, R, Dediesmulders, C, Engelen, J, Fryns, JP, Curfs, P, Oostra, BA: A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome. Hum Mol Genet 1994; 3: 615–620.Google Scholar
40. Siomi, H, Siomi, MC, Nussbaum, RL, Dreyfuss, G: The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell 1993; 74: 291–298.CrossRefGoogle ScholarPubMed
41. Ashley, C Jr, Wilkinson, KD, Reines, D, Warren, ST: FMR1 protein: Conserved RNP family domains and selective RNA binding. Science 1993; 262: 563–568.Google Scholar
42. De Boulle, K, Verkerk, AJ, Reyniers, E, Vits, L, Hendrickx, J, Van Roy, B, Van den Bos, F, de Graaff, E, Oostra, BA, Willems, PJ: A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet 1993; 3: 31–35.Google Scholar
43. Siomi, H, Choi, M, Siomi, MC, Nussbaum, RL, Dreyfuss, G: Essential role for KH domains in RNA binding: Impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome. Cell 1994; 77: 33–39.Google Scholar
44. Verheij, C, De Graaff, E, Bakker, CE, Willemsen, R, Willems, PJ, Meijer, N, Galjaard, H, Reuser, AJJ, Oostra, BA, Hogeveen, AT: Characterization of FMR1 proteins isolated from different tissues. Hum Mol Genet, in press.Google Scholar
45. La Spada, AR, Wilson, EM, Lubahn, DB, Harding, AE, Fischbeck, KH: Andiogen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352: 77–79.Google Scholar
46. Brook, JD, McCurrach, ME, Harley, HG, Buckler, AJ, Church, D, Aburatani, H, Hunter, K, Stanton, VP, Thirion, JP, Hudson, T, Sohn, R, Zemelman, B, Snell, RG, Rundle, SA, Crow, S, Davies, J, Shelboume, P, Buxton, J, Jones, C, Juvonen, V, Johson, K, Harper, PS, Shaw, DJ, Housman, DE: Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 1992; 68: 799–808.Google Scholar
47. Mahadevan, M, Tsilfidis, C, Saborin, L, Shutler, G, Amemiya, C, Jansen, G, Neville, C, Narang, M, Barcelo, J, OrHOy, K, Leblond, S, Earle-Macdonald, J, de Jong, P, Wieringa, B, Komeluk, RG: Myotonie dystrophy mutation: An unstable CTG repeat in the 3' untranslated region of the gene. Science 1992; 255: 1253–1255.CrossRefGoogle Scholar
48. Huntington, . A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993; 72: 971–983.Google Scholar
49. Orr, HT, Chung, M, Banfi, S, Kwiatkowski, TJ, Servadio, A, Beaudet, A, McCall, AE, Duvick, LA, Ranum, LPW, Zohgbi, HY: Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 1993; 4: 221–226.Google Scholar
50. Koide, R, Ikeuchi, T, Onodera, O, Tanaka, H, Igarashi, S, Endo, K, Takahashi, H, Kondo, R, Ishikawa, A, Hayashi, T, Saito, M, Tomoda, A, Miike, T, Naito, H, Ikuta, F, Tsuji, S: Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet 1994; 6: 9–13.Google Scholar
51. Nagafuchi, S, Yanagisawa, H, Sato, K, Shirayama, T, Ohsaki, E, Bundo, M, Takeda, T, Tadokoro, K, Kondo, I, Murayama, N: Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG repeat trinucleotide on chromosome 12p. Nat Genet 1994; 6: 14–18.Google Scholar
52. Knight, SJ, Flannery, AV, Hirst, MC, Campbell, L, Christodoulou, Z, Phelps, SR, Pointon, J, Middleton-Price, HR, Bamicoat, A, Pembrey, ME, Holland, J, Oostra, BA, Bobrow, M, Davies, KE: Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation. Cell 1993; 74: 127–134.CrossRefGoogle ScholarPubMed
53. Burke, JR, Wingfield, MS, Lewis, KE, Roses, AD, Lee, JE, Hulette, C, Pericak-Vance, MA, Vance, JM: The Haw River syndrome: Dentatorubropallidoluysian atrophy (DRPLA) in an African-American family. Nat Genet 1994; 7: 521–524.Google Scholar
54. Kawaguchi, Y, Okamoto, T, Taniwaki, M, Aizawa, M, Inoue, M, Katayama, S, Kawakami, H, Nakamura, S, Nishimura, M, Akiguchi, I, Kimura, J, Narumiya, S, Kakizuka, A: CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994; 8: 221–228.Google Scholar
55. Nancarrow, JK, Kremer, E, Holman, K, Eyre, H, Doggett, NA, Le Paslier, D, Callen, DF, Sutherland, GR, Richards, RI: Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis. Science 1994; 264: 1938–1941.Google Scholar
56. Parrish, JE, Oostra, BA, Verkerk, AJHM, Richards, CS, Spikes, AS, Shaffer, LG, Nelson, DL: Isolation of a GCC repeat showing expansion in FRAXF, a fragile site distal to FRAXA and FRAXE. Nat Genet 1994; 8: 229–235.Google Scholar
57. Sherman, SL, Morton, NE, Jacobs, PE, Turner, G: The marker (X) chromosome: A cytogenetic and genetic analysis. Ann Hum Genet 1984; 48: 21–37.Google Scholar
58. Sherman, SL, Jacobs, PA, Morton, NE, Froster-Iskenius, U, Howard-Peebles, PN, Nielsen, KB, Partington, NW, Sutherland, GR, Turner, G, Watson, M: Further segregation of the fragile X syndrome with special reference to transmitting males. Hum Genet 1985; 69: 289–299.Google Scholar
59. Richards, RI, Holman, K, Friend, K, Kremer, E, Hillen, D, Staples, A, Brown, WT, Goonewardena, P, Tarleton, J, Schwartz, C, Sutherland, GR: Evidence of founder chromosomes in fragile X syndrome. Nat Genet 1992; 1: 257–260.Google Scholar
60. Oudet, C, Mornet, E, Serre, JL, Thomas, F, Lentes-Zengerling, S, Kretz, C, Deluchat, C, Tejada, I, Boue, J, Boue, A, Mandel, JL: Linkage disequilibrium between the fragile X mutation and two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes. Am J Hum Genet 1993; 52: 297–304.Google Scholar
61. Hirst, MC, Knight, SJ, Christodoulou, Z, Grewal, PK, Fryns, JP, Davies, KE: Origins of the fragile X syndrome mutation. J Med Genet 1993; 30: 647–650.Google Scholar
62. Oudet, C, von Kuskull, H, Nordstrom, AM, Peippo, M, Mandel, JL: Striking founder effect for the fragile X syndrome in Finland. Eur J Hum Genet 1993 ; 1: 181–189.Google Scholar
63. Buyle, S, Reyniers, E, Vits, L, De Boulle, K, Handig, I, Wuyts, FL, Deelen, W, Halley, DJ, Oostra, BA, Willems, PJ: Founder effect in a Belgian-Dutch fragile X population. Hum Genet 1993; 92: 269–272.Google Scholar
64. Macpherson, JN, Bullman, H, Youings, SA, Jacobs, PA: Insert size and flanking haplotype in fragile X and normal populations – Possible multiple origins for the fragile X mutation. Hum Mol Genet 1994; 3: 399–405.CrossRefGoogle ScholarPubMed
65. Devys, D, Biancalana, V, Rousseau, F, Boue, J, Mandel, JL, Oberle, I: Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am J Med Genet 1992; 43: 208–216.Google Scholar
66. Willems, PJ, Van Roy, B, De Boulle, K, Vits, L, Reyniers, E, Beck, O, Dumon, JE, Verkerk, A, Oostra, B: Segregation of the fragile X mutation from an affected male to his normal daughter. Hum Mol Genet 1992; 1: 511–515.Google Scholar
67. Reyniers, E, Vits, L, De Boulle, K, Van Roy, B, Van Velzen, D, de Graaff, E, Verkerk, AJMH, Jorens, HZ, Darby, JK, Oostra, BA, Willems, PJ: The full mutation in the FMR-1 gene of male fragile X patients is absent in their sperm. Nat Genet 1993; 4: 143–146.Google Scholar
68. Bakker, CE, Verheij, C, Willemsen, R, Vanderhelm, R, Oerlemans, F, Vermey, M, Bygrave, A, Hoogeveen, AT, Oostra, BA, Reyniers, E, Deboulle, K, Dhooge, R, Cras, P, Van Velzen, D, Nagels, G, Martin, JJ, Dedeyn, PP, Darby, JK, Willems, PJ: Fmrl knockout mice: A model to study fragile X mental retardation. Cell 1994; 78: 23–33.Google Scholar
69. Hansen, RS, Canfield, TK, Lamb, MM, Gartier, SM, Laird, CD: Association of fragile X syndrome with delayed replication of the FMR1 gene. Cell 1993; 73: 1403–1409.Google Scholar
70. Richards, RI, Sutherland, GR: Dynamic mutations: A new class of mutations causing human disease. Cell 1992; 70: 709–712.Google Scholar
71. Richards, RI, Sutherland, GR: Simple repeat DNA is not replicated simply. Nat Genet 1994; 6: 1114–116.Google Scholar
72. Kunst, CB, Warren, ST: Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 1994; 77: 853–861.CrossRefGoogle ScholarPubMed
73. Hirst, MC, Grewal, PK, Davies, KE: Precursor arrays for triplet repeat expansion at the fragile X locus. Hum Mol Genet 1994; 3: 1553–1560.CrossRefGoogle ScholarPubMed
74. Eichler, EE, Holden, J, Popovich, BW, Reiss, AL, Snow, K, Thibodeau, SN, Richards, CS, Ward, PA, Nelson, DL: Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet 1994; 8: 88–94.CrossRefGoogle ScholarPubMed
75. Leach, FS, Nicolaides, NC, Papadopoulos, N, Liu, B, Jen, J, Parsons, R, Peltomaki, P, Sistonen, P, Aaltonen, LA, Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75: 1215–1225.Google Scholar
76. Bronner, CE, Baker, SM, Morrison, PT, Warren, G, Smith, LG, Lescoe, MK, Kane, M, Earabino, C,: Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 1994; 368: 258–261.Google Scholar
77. Nicolaides, NC, Papadopoulos, N, Liu, B, Wei, YF, Carter, KC, Ruben, SM, Rosen, CA, Haseltine, WA,: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994; 371: 75–80.Google Scholar
78. Hinds, HL, Ashley, CT, Sutcliffe, JS, Nelson, DL, Warren, ST, Housman, DE, Schalling M: Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat Genet 1993; 3: 36–43.Google Scholar
79. Bachner, D, Manca, A, Steinbach, P, Wohrle, D, Just, W, Vogel, W, Hameister, H, Poustka, A: Enhanced expression of the murine FMR1 gene during germ cell proliferation suggests a special function in both the male and the female gonad. Hum Mol Genet 1993; 2: 2043–2050.Google Scholar