Review Article : Genetics of Neurofibromatosis 1 and the NF1 Gene

Abstract

Neurofibromatosis 1 serves as a paradigm for understanding the principles of human genetics. The concepts of gene mutation, penetrance of the condition, variable clinical expressivity, mosaicism, age-dependent expression of clinical manifestations, and pleiotropy are evident in this autosomal dominant condition. The lack of genotype-phenotype correlation, except the whole-gene deletion phenotype, leads to speculation on modifiers of the haploinsufficient state of the NF1 gene product neurofibromin. The variant form of neurofibromatosis, neurofibromatosis Noonan's syndrome, suggests potential interaction of independent biochemical pathways. Identification of the NF1 gene led to the discovery of its role in ras signal transduction. Neurofibromin is a negative regulator of intracellular ras signaling. This observation now provides the framework for the development of rational medical therapies. In addition, knowledge of the molecular basis of the variable expression of clinical manifestations could provide better anticipatory guidance and more effective management of the medical complications that are associated with this condition. (J Child Neurol 2002;17:562-570).

Get full access to this article

View all access options for this article.

References

Korf B. : Diagnostic outcome in children with multiple café-au-lait spots. Pediatrics 1992;90:924-927.

Friedman JM : Neurofibromatosis 1: Clinical manifestations and diagnostic criteria. J Child Neurol 2002;17:548-554.

Easton DF , Ponder MA , Huson SM , et al: An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): Evidence for modifying genes. Am J Hum Genet 1993;53:305-313.

Easton DF : Genotype-phenotype relationships in neurofibromatosis type 1, in Upadhyaya M , Cooper DN (eds): Neurofibromatosis Type 1: From Genotype to Phenotype. Oxford, BIOS Scientific Publishers, 1998, 167-174.

Carey J. , Viskochil D. : Neurofibromatosis type 1: A model condition for the study of the molecular basis of variable expressivity in human disorders. Am J Med Genet 1999;89:7-13.

Kayes LM , Riccardi VM , Burke W. , et al: Large de novo DNA deletion in a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism. J Med Genet 1992;29:686-690.

Kayes L. , Burke W. , Riccardi VM , et al: Deletions spanning the neurofibromatosis 1 gene: Identification and phenotype of five patients. Am J Hum Genet 1994;54:424-436.

Tonsgard J. , Yelavarthi K. , Cushner S. , et al: Do NF1 gene deletions result in a characteristic phenotype? Am J Med Genet 1997;73: 80-86.

Wu B-L. , Austin MA , Schneider GH , et al: Deletion of the entire NF1 gene detected by FISH: Four deletion patients associated with severe manifestations. Am J Med Genet 1995;59:528-535.

10.

Wu B-L. , Schneider GH , Korf BR : Deletion of the entire NF1 gene causing distinct manifestations in a family. Am J Med Genet 1997; 69:98-101.

11.

Cnossen MH , van der Est MN , Breuning MH , et al: Deletions spanning the neurofibromatosis type 1 gene: Implications for genotype-phenotype correlations in neurofibromatosis type 1? Hum Mutation 1997;9:458-464.

12.

Leppig KA , Kaplan P. , Viskochil D. , et al: Familial neurofibromatosis 1 microdeletions: Cosegregation with distinct facial phenotype and early onset of cutaneous neurofibromata. Am J Med Genet 1997;73:197-204.

13.

Upadhyaya M. , Cooper D. : The mutational spectrum in neurofibromatosis 1 and its underlying mechanisms , in Upadhyaya M , Cooper DN (eds): Neurofibromatosis Type 1: From Genotype to Phenotype. Oxford: BIOS Scientific Publishers, 1998, 65-88.

14.

Riccardi VM , Eichner JE : Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore: Johns Hopkins University Press, 1986.

15.

Ruggieri M. , Huson SM : The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 2001;56: 1433-1443.

16.

Colman S. , Rasmussen S. , Ho V. , et al: Somatic mosaicism in a patient with neurofibromatosis type 1 . Am J Hum Genet 1996;58: 484-490.

17.

Ainsworth P. , Chakraborty P. , Weksberg R. : Example of somatic mosaicism in a series of de novo neurofibromatosis type 1 cases due to a maternally derived deletion . Hum Mutat 1997;9:452-457.

18.

Wu B-L. , Boles R. , Yaari H. , et al: Somatic mosaicism for deletion of the entire NF1 gene identified by FISH. Hum Genet 1997;99: 209-213.

19.

Lazaro C. , Gaona A. , Lynch M. , et al: Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Am J Hum Genet 1995;57: 1044-1049.

20.

Tinschert S. , Naumann I. , Stegmann E. , et al: Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet 2000;8:455-459.

21.

Allanson JE , Hall JG , Van Allen MI : Noonan phenotype associated with neurofibromatosis . Am J Med Genet 1985;21:457-462.

22.

Watson GH : Pulmonary stenosis, café-au-lait spots, and dull intelligence. Arch Dis Child 1967;42:303-307.

23.

Allanson JE , Upadhyaya M. , Watson G. , et al: Watson syndrome: Is it a subtype of type 1 neurofibromatosis? J Med Genet 1991 ;28: 752-756.

24.

Carey JC : Neurofibromatosis-Noonan syndrome. Am J Med Genet 1998;75:263-264.

25.

Carey J. , Stevenson D. , Ota M. , et al: Is there an NF/Noonan syndrome ? Part 2: Documentation of the clinical and molecular aspects of an important family. Proc Greenwood Genet Cent 1998; 17:52-53.

26.

Tassabehji M. , Strachan T. , Sharland M. , et al: Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. Am JHum Genet 1993;53:90-95.

27.

Tartaglia M. , Mehler EL , Goldberg R. , et al: Mutations in PTPN1 , encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-468.

28.

Brunner HG , Hulsebos T. , Steijlen PM , et al: Exclusion of the neurofibromatosis 1 locus in a family with inherited café-au-lait spots. Am J Med Genet 1993;46:472-474.

29.

Charrow J. , Listernick R. , Ward K. : Autosomal dominant multiple café-au-lait spots and neurofibromatosis-1: Evidence of non-linkage. Am J Med Genet 1993;45:606-608.

30.

Abeliovich D. , Gelman-Kohan Z. , Silverstein S. , et al: Familial café-au-lait spots: A variant of neurofibromatosis type 1. J Med Genet 1995 ;32:985-986.

31.

Pulst SM , Riccardi VM , Fain P. , et al: Familial spinal neurofibromatosis: Clinical and DNA linkage analysis. Neurology 1991;41: 1923-1925.

32.

Poyhonen M. , Leisti E-L. , Kytola S. , et al: Hereditary spinal neurofibromatosis: A rare form of NF1? J Med Genet 1997;34:184-187.

33.

Ars E. , Kruyer H. , Gaona A. , et al: A clinical variant of neurofibromatosis type 1: Familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 1988;62:834-841.

34.

Viskochil D. : The structure and function of the NF1 gene: Molecular pathophysiology, in Friedman JM , Gutmann DH , MacCollin M , Riccardi VM (eds): Neurofibromatosis: Phenotype, Natural History, and Pathogenesis, 3rd ed. Baltimore and London, Johns Hopkins University Press. 1999, 119-141.

35.

Hajra A. , Martin-Gallardo A. , Tarle S. , et al: DNA sequences in the promoter region of the NF1 gene are highly conserved between human and mouse. Genomics 1994;21:649-652.

36.

Mancini DB , Singh SM , Archer TK , et al: Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors. Oncogene 1999;18: 4108-4119.

37.

Horan MP , Cooper DN , Upadhyaya M. : Hypermethylation of the neurofibromatosis type 1 (NF1) gene promoter is not a common event in the inactivation of the NF1 gene in NF1-specific tumours . Hum Genet 2000;107:33-39.

38.

Skuse GR , Cappione AJ , Sowden M. , et al: The neurofibromatosis type I messenger RNA undergoes base-modification RNA editing. Nucleic Acids Res 1996;24:478-485.

39.

Mukhopadhyay D. , Anant S. , Lee RM , et al: C ⇨ U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme. Am J Hum Genet 2002; 70:38-50.

40.

Viskochil D. : Neurofibromatosis 1. Am J Med Genet 1999;89:v-viii.

41.

Lopez-Correa C. , Brems H. , Lazaro C. , et al: Molecular studies in 20 submicroscopic neurofibromatosis type 1 gene deletions. Hum Mutat 1999;14:387-393.

42.

Dorschner MO , Sybert VP , Weaver M. , et al: NF1 microdeletion breakpoints are clustered at flanking repetitive sequences. Hum Mol Genet 2000;9:35-46.

43.

Jenne DE , Tinschert S. , Reimann H. , et al: Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions. Am J Hum Genet 2001;69:516-527.

44.

Lopez-Correa C. , Dorschner M. , Brems H. , et al: Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet 2001;10:1387-1392.

45.

Mikol D. , Gulcher J. , Stefansson K. : The oligodendrocyte myeline glycoprotein belongs to a distinct family of proteins and contains the HNK-1 carbohydrate. J Cell Biol 1990;110:471-480.

46.

Habib AA , Gulcher JR , Hognason T. , et al: The Omgp gene, a second growth suppressor within the NF1 gene . Oncogene 1998;16: 1525-1531.

47.

Purandare S. , Huntsman-Breidenbach H. , Li Y. , et al: Identification of neurofibromatosis 1 (NFI ) homologous loci by direct sequencing, fluorescence in situ hybridization and PCR amplification of somatic cell hybrids. Genomics 1995;30:476-485.

48.

Hulsebos T. , Bijlereld E. , Riegman P. , et al: Identification and characterization of NFl-related loci on human chromosomes 22, 14, and 2. Hum Genet 1996;98:7-11.

49.

Regnier V. , Meddeb M. , Lecointre G. , et al: Emergence and scattering of multiple neurofibromatosis (NF1)-related sequences during hominoid evolution suggest a process of pericentromeric interchromosomal transposition. Hum Mol Genet 1997;6:9-16.