Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1996 Mar;58(3):484–490.

Somatic mosaicism in a patient with neurofibromatosis type 1.

S D Colman 1, S A Rasmussen 1, V T Ho 1, C R Abernathy 1, M R Wallace 1
PMCID: PMC1914580  PMID: 8644707

Abstract

Using loss of heterozygosity analysis, a method designed to detect moderate to large gene deletions, we have identified a new-mutation neurofibromatosis type 1 (NF1) patient who is somatically mosaic for a large maternally derived deletion in the NF1 gene region. The deletion extends at least from exon 4 near the 5' end of the gene to intron 39 near the 3' end. The gene-coding region is, therefore, mostly or entirely deleted, encompassing a loss of > or = 100 kb. We hypothesize that the deletion occurred at a relatively early developmental timepoint, since signs of NF1 in this patient are not confined to a specific body region, as seen in "segmental" NF, and since both mesodermally and ectodermally derived cells are affected. This report provides the first molecular evidence of somatic mosaicism in NF1 and, taken together with a recent report of germ-line mosaicism in NF1, adds credence to the concept that mosaicism plays an important role in phenotypic and genetic aspects of NF1 and may even be a relatively common phenomenon.

Full text

PDF
485

Images in this article

486Figure 1
on p.486
486Figure 2
on p.486
487Figure 3
on p.487
487Figure 4
on p.487

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abernathy C., Colman S. D., Wallace M. R. A PCR-based test for a polymorphism within the human NF1 gene. Clin Genet. 1994 Jun;45(6):313–313. doi: 10.1111/j.1399-0004.1994.tb04038.x. [DOI] [PubMed] [Google Scholar]
  2. Bakker E., Veenema H., Den Dunnen J. T., van Broeckhoven C., Grootscholten P. M., Bonten E. J., van Ommen G. J., Pearson P. L. Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations. J Med Genet. 1989 Sep;26(9):553–559. doi: 10.1136/jmg.26.9.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernards A., Gusella J. F. The importance of genetic mosaicism in human disease. N Engl J Med. 1994 Nov 24;331(21):1447–1449. doi: 10.1056/NEJM199411243312110. [DOI] [PubMed] [Google Scholar]
  4. Boltshauser E., Stocker H., Mächler M. Neurofibromatosis type 1 in a child of a parent with segmental neurofibromatosis (NF-5). Neurofibromatosis. 1989;2(4):244–245. [PubMed] [Google Scholar]
  5. Bourn D., Carter S. A., Evans D. G., Goodship J., Coakham H., Strachan T. A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals. Am J Hum Genet. 1994 Jul;55(1):69–73. [PMC free article] [PubMed] [Google Scholar]
  6. Colman S. D., Williams C. A., Wallace M. R. Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat Genet. 1995 Sep;11(1):90–92. doi: 10.1038/ng0995-90. [DOI] [PubMed] [Google Scholar]
  7. Fishler K., Koch R. Mental development in Down syndrome mosaicism. Am J Ment Retard. 1991 Nov;96(3):345–351. [PubMed] [Google Scholar]
  8. Hall J. G. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. 1988 Oct;43(4):355–363. [PMC free article] [PubMed] [Google Scholar]
  9. Hirschhorn R., Yang D. R., Israni A., Huie M. L., Ownby D. R. Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery. Am J Hum Genet. 1994 Jul;55(1):59–68. [PMC free article] [PubMed] [Google Scholar]
  10. Hoff M., Nakamura Y., Holm T., Ballard L., O'Connell P., Leppert M., Lathrop G. M., Lalouel J. M., White R. Isolation and mapping of a polymorphic DNA sequence pHHH202 on chromosome 17 [D17S33]. Nucleic Acids Res. 1988 Jan 25;16(2):781–781. doi: 10.1093/nar/16.2.781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hoffmeyer S., Assum G. An RsaI polymorphism in the transcribed region of the neurofibromatosis (NF1)-gene. Hum Genet. 1994 Apr;93(4):481–482. doi: 10.1007/BF00201684. [DOI] [PubMed] [Google Scholar]
  12. Jadayel D., Fain P., Upadhyaya M., Ponder M. A., Huson S. M., Carey J., Fryer A., Mathew C. G., Barker D. F., Ponder B. A. Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature. 1990 Feb 8;343(6258):558–559. doi: 10.1038/343558a0. [DOI] [PubMed] [Google Scholar]
  13. Jorde L. B., Watkins W. S., Viskochil D., O'Connell P., Ward K. Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping. Am J Hum Genet. 1993 Nov;53(5):1038–1050. [PMC free article] [PubMed] [Google Scholar]
  14. Kayes L. M., Burke W., Riccardi V. M., Bennett R., Ehrlich P., Rubenstein A., Stephens K. Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients. Am J Hum Genet. 1994 Mar;54(3):424–436. [PMC free article] [PubMed] [Google Scholar]
  15. Kontusaari S., Tromp G., Kuivaniemi H., Stolle C., Pope F. M., Prockop D. J. Substitution of aspartate for glycine 1018 in the type III procollagen (COL3A1) gene causes type IV Ehlers-Danlos syndrome: the mutated allele is present in most blood leukocytes of the asymptomatic and mosaic mother. Am J Hum Genet. 1992 Sep;51(3):497–507. [PMC free article] [PubMed] [Google Scholar]
  16. Lázaro C., Gaona A., Estivill X. Two CA/GT repeat polymorphisms in intron 27 of the human neurofibromatosis (NF1) gene. Hum Genet. 1994 Mar;93(3):351–352. doi: 10.1007/BF00212039. [DOI] [PubMed] [Google Scholar]
  17. Lázaro C., Ravella A., Gaona A., Volpini V., Estivill X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med. 1994 Nov 24;331(21):1403–1407. doi: 10.1056/NEJM199411243312102. [DOI] [PubMed] [Google Scholar]
  18. Madisen L., Hoar D. I., Holroyd C. D., Crisp M., Hodes M. E. DNA banking: the effects of storage of blood and isolated DNA on the integrity of DNA. Am J Med Genet. 1987 Jun;27(2):379–390. doi: 10.1002/ajmg.1320270216. [DOI] [PubMed] [Google Scholar]
  19. Marchuk D. A., Saulino A. M., Tavakkol R., Swaroop M., Wallace M. R., Andersen L. B., Mitchell A. L., Gutmann D. H., Boguski M., Collins F. S. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics. 1991 Dec;11(4):931–940. doi: 10.1016/0888-7543(91)90017-9. [DOI] [PubMed] [Google Scholar]
  20. Martin-Gallardo A., Marchuk D. A., Gocayne J., Kerlavage A. R., McCombie W. R., Venter J. C., Collins F. S., Wallace M. R. Sequencing and analysis of genomic fragments from the NF1 locus. DNA Seq. 1992;3(4):237–243. doi: 10.3109/10425179209034023. [DOI] [PubMed] [Google Scholar]
  21. Reyniers E., De Boulle K., Marchuk D. A., Andersen L. B., Collins F. S., Willems P. J. An EcoRI RFLP in the 5' region of the human NF1 gene. Hum Genet. 1993 Dec;92(6):631–631. doi: 10.1007/BF00420953. [DOI] [PubMed] [Google Scholar]
  22. Riccardi V. M., Lewis R. A. Penetrance of von Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. Am J Hum Genet. 1988 Feb;42(2):284–289. [PMC free article] [PubMed] [Google Scholar]
  23. Saito K., Ikeya K., Kondo E., Komine S., Komine M., Osawa M., Aikawa E., Fukuyama Y. Somatic mosaicism for a DMD gene deletion. Am J Med Genet. 1995 Mar 13;56(1):80–86. doi: 10.1002/ajmg.1320560118. [DOI] [PubMed] [Google Scholar]
  24. Schmickel R. D. Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr. 1986 Aug;109(2):231–241. doi: 10.1016/s0022-3476(86)80377-8. [DOI] [PubMed] [Google Scholar]
  25. Shannon K. M., O'Connell P., Martin G. A., Paderanga D., Olson K., Dinndorf P., McCormick F. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med. 1994 Mar 3;330(9):597–601. doi: 10.1056/NEJM199403033300903. [DOI] [PubMed] [Google Scholar]
  26. Stephens K., Kayes L., Riccardi V. M., Rising M., Sybert V. P., Pagon R. A. Preferential mutation of the neurofibromatosis type 1 gene in paternally derived chromosomes. Hum Genet. 1992 Jan;88(3):279–282. doi: 10.1007/BF00197259. [DOI] [PubMed] [Google Scholar]
  27. Viskochil D., Buchberg A. M., Xu G., Cawthon R. M., Stevens J., Wolff R. K., Culver M., Carey J. C., Copeland N. G., Jenkins N. A. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990 Jul 13;62(1):187–192. doi: 10.1016/0092-8674(90)90252-a. [DOI] [PubMed] [Google Scholar]
  28. Wallis G. A., Starman B. J., Zinn A. B., Byers P. H. Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the alpha 1(I) gene (COL1A1) of type I collagen in a parent. Am J Hum Genet. 1990 Jun;46(6):1034–1040. [PMC free article] [PubMed] [Google Scholar]
  29. Xu G. F., Nelson L., O'Connell P., White R. An Alu polymorphism intragenic to the neurofibromatosis type 1 gene (NF1). Nucleic Acids Res. 1991 Jul 11;19(13):3764–3764. doi: 10.1093/nar/19.13.3764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Zlotogora J. Mutations in von Recklinghausen neurofibromatosis: an hypothesis. Am J Med Genet. 1993 Apr 15;46(2):182–184. doi: 10.1002/ajmg.1320460217. [DOI] [PubMed] [Google Scholar]
  31. van Essen A. J., Abbs S., Baiget M., Bakker E., Boileau C., van Broeckhoven C., Bushby K., Clarke A., Claustres M., Covone A. E. Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study. Hum Genet. 1992 Jan;88(3):249–257. doi: 10.1007/BF00197255. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES