Advertisement

Human Genetics

, Volume 117, Issue 4, pp 376–382 | Cite as

FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure

  • Karla L. Bretherick
  • Margo R. Fluker
  • Wendy P. Robinson
Original Investigation

Abstract

Premature ovarian failure (POF) is the occurrence of menopause before the age of 40 and affects 1% of the female population. Whereas the etiology of POF is largely unexplained, FMR1 premutation carriers are known to be at increased risk of POF compared with the general population. The FMR1 premutation alleles have 55–200 copies of a CGG repeat in the 5′ untranslated region of the FMR1 gene. However, functional effects on gene expression may occur even for repeat sizes in what has been considered the “normal” range. To evaluate the role of the FMR1 repeat in POF, repeat sizes were examined in 53 women with idiopathic POF, 161 control women from the general population, and 21 women with proven fertility at an advanced maternal age. A significant increase in the number of FMR1 alleles between and including 35 and 54 CGG repeats was found in the POF patient population; 15 of 106 (14.2%) POF alleles were between and including 35 and 54 repeats, whereas only 21 of 322 (6.5%) alleles in the general population (P=0.02) and 2 of 42 (4.8%) alleles from women with proven late fertility (P=0.09) were of this size (P=0.01 versus combined controls). The effect was also significant for comparisons of genotype repeat size (repeat size weighted by the relative activity of the two FMR1 alleles) and biallelic mean (average size of the two alleles). These results are clinically relevant and suggest that the FMR1 gene plays a more significant role in the incidence of POF than has previously been thought.

Keywords

Premature Ovarian Failure Premutation Carrier Premutation Allele Androgen Receptor Locus Premature Ovarian Failure Patient 
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.

Notes

Acknowledgements

We thank the POF patients for participating in this study and Ruby Jiang for technical assistance. This work was supported by Canadian Institutes of Health Research Grant MOP-38051 to W.P.R. K.B. is funded by the Institute of Genetics at the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research, and the Interdisciplinary Women’s Reproductive Health training program at the BC Research Institute for Children’s and Women’s Health.

References

  1. Allen EG, Weiya He, Yadav-Shah M, Sherman S (2004) A study of the distributional characteristics of FMR1 transcript level in 238 individuals. Hum Genet 114:439–447CrossRefPubMedGoogle Scholar
  2. Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, Holden JJA, Yang KT, Lee C, Hudson R, et al (1999) Fragile X premutation is a significant risk factor for premature ovarian failure: the international collaborative POF in fragile X study—preliminary data. Am J Med Genet 83:322–325CrossRefPubMedGoogle Scholar
  3. Beever CL (2002) Clinical and molecular aspects of the association of skewed X-chromosome inactivation and recurrent spontaneous abortion. MSc Thesis, University of British Columbia, CanadaGoogle Scholar
  4. Beever CL, Stephenson MD, Penaherrera M, Jiang R, Kalousek DK, Hayden M, Field L, Brown CJ, Robinson WP (2003) Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies. Am J Hum Genet 72:399–407Google Scholar
  5. Chen LS, Tassone F, Sahota P, Hagerman PJ (2003) The (CGG) n repeat element within the 5′ untranslated region of the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter. Hum Mol Genet 12:3067–3074CrossRefPubMedGoogle Scholar
  6. Coulam CB, Adamson SC, Annegers JF (1986) Incidence of premature ovarian failure. Obstet Gynecol 67:604–606PubMedGoogle Scholar
  7. Dawson AJ, Chodirker BN, Chudley AE (1995) Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. Biochem Mol Med 56:63–69CrossRefPubMedGoogle Scholar
  8. Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP (2004) RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science 303:383–387CrossRefPubMedGoogle Scholar
  9. Fu YH, Kuhl DP, Pizzuti M, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJ, Holden JJ, Fenwick RG, Warren ST, et al (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058CrossRefPubMedGoogle Scholar
  10. Gold B, Radu D, Balanko A, Chiang C (2000) Diagnosis of fragile X syndrome by Southern blot hybridization using a chemiluminescent probe: a laboratory protocol. Mol Diagn 5:169–178CrossRefPubMedGoogle Scholar
  11. Greco CM, Hagerman RJ, Tassone F, Chudley AE, Del Bigio MR, Jacquemont S, Leehey M, Hagerman PJ (2002) Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125:1760–1771CrossRefPubMedGoogle Scholar
  12. Hagerman PJ, Hagerman RJ (2004) The fragile X premutation: a maturing perspective. Am J Hum Genet 74:805–816Google Scholar
  13. Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ (2001) Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57:127–130Google Scholar
  14. Hatakeyama C, Anderson CL, Beever CL, Penaherrera MS, Brown CJ, Robinson WP (2004) The dynamics of X-inactivation skewing as women age. Clin Genet 66:327–332CrossRefPubMedGoogle Scholar
  15. Hecimovic S, Barisic I, Muller A, Petkovic I, Baric I, Ligutic I, Pavelic K (1997) Expand long PCR for fragile X mutation detection. Clin Genet 52:147–154PubMedGoogle Scholar
  16. Hundscheid RL, Braat DDM, Kiemeney LALM, Smits APT, Thomas CMG (2001) Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives. Hum Reprod 16:457–462CrossRefPubMedGoogle Scholar
  17. Jin P, Zarnescu DC, Zhang F, Pearson CE, Lucchesi JC, Moses K, Warren ST (2003) RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39:739–747CrossRefPubMedGoogle Scholar
  18. Kenneson A, Zhang F, Hagedorn CH, Wang ST (2001) Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate and premutation carriers. Hum Mol Genet 10:1449–1454CrossRefPubMedGoogle Scholar
  19. Larsen LA, Gronskov K, Norgaard-Pedersen B, brondum-Nielsen K, Hasholt L, Vuust J (1997) High-throughput analysis of fragile X (CGG)n alleles in the normal and premutation range by PCR amplification and automated capillary electrophoresis. Hum Genet 100:564–568CrossRefPubMedGoogle Scholar
  20. McKinlay S, Jefferys M, Thompson B (1972) An investigation of the age at menopause. J Biosoc Sci 4:161–173PubMedGoogle Scholar
  21. Murray A (2000) Premature ovarian failure and the FMR1 gene. Sem Reprod Med 18:59–66CrossRefGoogle Scholar
  22. Murray A, Webb J, MacSwiney F, Shipley EL, Morton NE, Conway GS (1999) Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod 14:1217–1218CrossRefPubMedGoogle Scholar
  23. Murray A, Ennis S, MacSwiney F, Webb J, Morton NE (2000). Reproductive and menstrual history of females with fragile X expansions. Eur J Hum Genet 8:247–252Google Scholar
  24. Nolin S, Brown WT, Glicksman A, Houck GE, Gargano AD, Sullivan A, Biancalana V, Brondum-Nielsen K, Hjalgrim H, Holinski-Feder E, Kooy F, Longshore J, Macpherson J, Mandel JL, Matthijs G, Rousseau F, Steinbach P, Vaisanen ML, Koskull H von, Sherman SL (2003) Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 72:454–464CrossRefPubMedGoogle Scholar
  25. Oberle I, Rousseau F, Heitz D, Kretz C, Devys D, Hanauer A, Boue J, Bertheas MF, Mandel JL (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252:1097–1102PubMedGoogle Scholar
  26. Pang CP, Poon PM, Chen QL, Lai KY, Yin CH, Zhao Z, Zhong N, Lau CH, Lam S, Wong CK, Brown WT (1999) Trinucleotide CGG repeat in the FMR1 gene in Chinese mentally retarded patients. Am J Med Genet 84:179–183CrossRefPubMedGoogle Scholar
  27. Partington MW, Moore DY, Turner GM (1996) Confirmation of early menopause in fragile X carriers. Am J Med Genet 64:370–372CrossRefPubMedGoogle Scholar
  28. Patsalis PC, Sismani C, Hettinger JA, Holden J, Lawson JS, Chalifoux M, Wing M, Walker M, Leggo J (1999) Frequencies of “grey zone” and premutation size FMR1 CGG-repeat alleles in patients with developmental disability in Cyprus and Canada. Am J Med Genet 84:195–197Google Scholar
  29. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66:817–822CrossRefPubMedGoogle Scholar
  30. Saha S, Karmakar P, Chatterjee C, Banerjee D, Das S, Dasgupta UB (2001) Fragile X syndrome in Calcutta, India. Ann Clin Biochem 38:264–271CrossRefPubMedGoogle Scholar
  31. Schwartz CF, Dean J, Howard-Peebles PN, Bugge M, Mikkelsen M, Tommerup N, Hull C, Hagerman R, Holden JJA, Stevenson RE (1994) Obstetrical and gynaecological complications in fragile X carriers: a multicenter study. Am J Med Genet 51:400–402PubMedGoogle Scholar
  32. Sharma D, Gupta M, Thelma BK (2001) Expansion mutation frequency and CGG/GCC repeat polymorphism in FMR1 and FMR2 genes in an Indian population. Gen Epidemiol 20:129–144CrossRefGoogle Scholar
  33. Sherman SL (2000) Premature ovarian failure in the fragile X syndrome. Am J Med Genet 97:189–194CrossRefPubMedGoogle Scholar
  34. Snow K, Doud LK, Hagerman R, Pergolizzi RG, Erster SH, Thibideau SN (1993) Analysis of a CGG sequence at the FMR-1 locus in fragile X Families and the general population. Am J Hum Genet 53:1217–1228Google Scholar
  35. Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, Yadav-Shah M, Sherman SL (2005) Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 20:402–412CrossRefPubMedGoogle Scholar
  36. Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ (2000a) Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in fragile X syndrome. Am J Hum Genet 66:6–15Google Scholar
  37. Tassone F, Hagerman RJ, Chamberlain WD, Hagerman PJ (2000b) Transcription of the FMR1 gene in individuals with fragile X syndrome. Am J Med Genet 97:195–203Google Scholar
  38. Tassone F, Hagerman RJ, Taylor AK, Mills JB Harris SW, Gane LW, Hagerman PJ (2000c) Clinical involvement and protein expression in individuals with the FMR1 premutation. Am J Med Genet 91:144–152Google Scholar
  39. Tassone F, Iwahashi C, Hagerman PJ (2004) FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA Biol 1:103–105Google Scholar
  40. Tzeng CC, ChoWC, Kuo PL, Chen RM (1999) Pilot fragile X screening in normal population of Taiwan. Diagn Mol Pathol 8:152–156CrossRefPubMedGoogle Scholar
  41. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914CrossRefPubMedGoogle Scholar
  42. Willemsen R, Hoogeveen-Westerveld M, Ries S, Holstege J, Severijnen L, Nieuwenhuizen IM, Schrier M, Mientjes EJ, Oostra BA (2003) The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet 12:949–959CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Karla L. Bretherick
    • 2
    • 3
  • Margo R. Fluker
    • 4
    • 5
  • Wendy P. Robinson
    • 1
    • 2
    • 3
  1. 1.BC Research Institute for Children’s and Women’s HealthVancouverCanada
  2. 2.Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  3. 3.BC Research Institute for Children’s and Women’s HealthVancouverCanada
  4. 4.Department of Obstetrics and GynaecologyUniversity of British ColumbiaVancouverCanada
  5. 5.Genesis Fertility Centre VancouverCanada

Personalised recommendations