• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajhgLink to Publisher's site
Am J Hum Genet. Sep 1996; 59(3): 529–539.
PMCID: PMC1914910

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.

Abstract

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, other benign neural tumors, and cataracts. Patients in some families develop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutations result in a truncated protein and severe NF2. To look for additional mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice-site mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnosis, numbers of meningiomas, spinal and skin tumors, and presence of cataracts and retinal abnormalities. We compared clinical findings in patients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P < or = .05) for nearly every variable. Patients with nonsense or frameshift mutations were younger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and frameshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences between the two groups were observed only for mean ages at onset and at diagnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patients from five families with four different nonsense mutations. This finding, which may represent a new genotype-phenotype correlation, merits further study.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allen JC, Eldridge R, Young D. Early-onset neuroma: genetic, clinical and nosologic aspects. Birth Defects Orig Artic Ser. 1974;10(10):171–184. [PubMed]
  • Anderson MA, Gusella JF. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro. 1984 Nov;20(11):856–858. [PubMed]
  • Arai E, Ikeuchi T, Nakamura Y. Characterization of the translocation breakpoint on chromosome 22q12.2 in a patient with neurofibromatosis type 2 (NF2). Hum Mol Genet. 1994 Jun;3(6):937–939. [PubMed]
  • Bijlsma EK, Merel P, Fleury P, van Asperen CJ, Westerveld A, Delattre O, Thomas G, Hulsebos TJ. Family with neurofibromatosis type 2 and autosomal dominant hearing loss: identification of carriers of the mutated NF2 gene. Hum Genet. 1995 Jul;96(1):1–5. [PubMed]
  • Bourn D, Carter SA, Evans DG, 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]
  • Bourn D, Carter SA, Mason S, Gareth D, Evans R, Strachan T. Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. Hum Mol Genet. 1994 May;3(5):813–816. [PubMed]
  • Bouzas EA, Parry DM, Eldridge R, Kaiser-Kupfer MI. Familial occurrence of combined pigment epithelial and retinal hamartomas associated with neurofibromatosis 2. Retina. 1992;12(2):103–107. [PubMed]
  • Caspari R, Friedl W, Mandl M, Möslein G, Kadmon M, Knapp M, Jacobasch KH, Ecker KW, Kreissler-Haag D, Timmermanns G, et al. Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer. Lancet. 1994 Mar 12;343(8898):629–632. [PubMed]
  • Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G, et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66–75. [PubMed]
  • Cotlier E. Café-au-lait spots of the fundus in neurofibromatosis. Arch Ophthalmol. 1977 Nov;95(11):1990–1992. [PubMed]
  • Davies DR, Armstrong JG, Thakker N, Horner K, Guy SP, Clancy T, Sloan P, Blair V, Dodd C, Warnes TW, et al. Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet. 1995 Nov;57(5):1151–1158. [PMC free article] [PubMed]
  • Evans DG, Bourn D, Wallace A, Ramsden RT, Mitchell JD, Strachan T. Diagnostic issues in a family with late onset type 2 neurofibromatosis. J Med Genet. 1995 Jun;32(6):470–474. [PMC free article] [PubMed]
  • Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R. A clinical study of type 2 neurofibromatosis. Q J Med. 1992 Aug;84(304):603–618. [PubMed]
  • Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, Newton V, Strachan T, Ramsden R, Harris R. A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet. 1992 Dec;29(12):841–846. [PMC free article] [PubMed]
  • Font RL, Moura RA, Shetlar DJ, Martinez JA, McPherson AR. Combined hamartoma of sensory retina and retinal pigment epithelium. Retina. 1989;9(4):302–311. [PubMed]
  • Good WV, Erodsky MC, Edwards MS, Hoyt WF. Bilateral retinal hamartomas in neurofibromatosis type 2. Br J Ophthalmol. 1991 Mar;75(3):190–190. [PMC free article] [PubMed]
  • Jacoby LB, MacCollin M, Louis DN, Mohney T, Rubio MP, Pulaski K, Trofatter JA, Kley N, Seizinger B, Ramesh V, et al. Exon scanning for mutation of the NF2 gene in schwannomas. Hum Mol Genet. 1994 Mar;3(3):413–419. [PubMed]
  • Kaiser-Kupfer MI, Freidlin V, Datiles MB, Edwards PA, Sherman JL, Parry D, McCain LM, Eldridge R. The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. Arch Ophthalmol. 1989 Apr;107(4):541–544. [PubMed]
  • Kanter WR, Eldridge R, Fabricant R, Allen JC, Koerber T. Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology. 1980 Aug;30(8):851–859. [PubMed]
  • Kaye LD, Rothner AD, Beauchamp GR, Meyers SM, Estes ML. Ocular findings associated with neurofibromatosis type II. Ophthalmology. 1992 Sep;99(9):1424–1429. [PubMed]
  • Kilpatrick TJ, Hjorth RJ, Gonzales MF. A case of neurofibromatosis 2 presenting with a mononeuritis multiplex. J Neurol Neurosurg Psychiatry. 1992 May;55(5):391–393. [PMC free article] [PubMed]
  • Kluwe L, Mautner VF. A missense mutation in the NF2 gene results in moderate and mild clinical phenotypes of neurofibromatosis type 2. Hum Genet. 1996 Feb;97(2):224–227. [PubMed]
  • Kluwe L, Pulst SM, Köppen J, Mautner VF. A 163-bp deletion in the neurofibromatosis 2 (NF2) gene associated with variant phenotypes [corrected]. Hum Genet. 1995 Apr;95(4):443–446. [PubMed]
  • Landau K, Dossetor FM, Hoyt WF, Muci-Mendoza R. Retinal hamartoma in neurofibromatosis 2. Arch Ophthalmol. 1990 Mar;108(3):328–329. [PubMed]
  • Landau K, Yaşargil GM. Ocular fundus in neurofibromatosis type 2. Br J Ophthalmol. 1993 Oct;77(10):646–649. [PMC free article] [PubMed]
  • Lee DK, Abbott ML. Familial central nervous system neoplasia. Case report of a family with von Recklinghausen's neurofibromatosis. Arch Neurol. 1969 Feb;20(2):154–160. [PubMed]
  • Lekanne Deprez RH, Bianchi AB, Groen NA, Seizinger BR, Hagemeijer A, van Drunen E, Bootsma D, Koper JW, Avezaat CJ, Kley N, et al. Frequent NF2 gene transcript mutations in sporadic meningiomas and vestibular schwannomas. Am J Hum Genet. 1994 Jun;54(6):1022–1029. [PMC free article] [PubMed]
  • MacCollin M, Mohney T, Trofatter J, Wertelecki W, Ramesh V, Gusella J. DNA diagnosis of neurofibromatosis 2. Altered coding sequence of the merlin tumor suppressor in an extended pedigree. JAMA. 1993 Nov 17;270(19):2316–2320. [PubMed]
  • MacCollin M, Ramesh V, Jacoby LB, Louis DN, Rubio MP, Pulaski K, Trofatter JA, Short MP, Bove C, Eldridge R, et al. Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet. 1994 Aug;55(2):314–320. [PMC free article] [PubMed]
  • Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med. 1988 Mar 17;318(11):684–688. [PubMed]
  • Mérel P, Hoang-Xuan K, Sanson M, Bijlsma E, Rouleau G, Laurent-Puig P, Pulst S, Baser M, Lenoir G, Sterkers JM, et al. Screening for germ-line mutations in the NF2 gene. Genes Chromosomes Cancer. 1995 Feb;12(2):117–127. [PubMed]
  • Mérel P, Hoang-Xuan K, Sanson M, Moreau-Aubry A, Bijlsma EK, Lazaro C, Moisan JP, Resche F, Nishisho I, Estivill X, et al. Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas. Genes Chromosomes Cancer. 1995 Jul;13(3):211–216. [PubMed]
  • Mori M, Morisaki S, Hazama R, Tsujihata M, Nagataki S, Yonekura M, Moriyama T, Mori K. [A family of von Recklinghausen's neurofibromatosis complicated by mononeuritis multiplex, bilateral acoustic neurinomas, and falx and spinal meningiomas]. No To Shinkei. 1985 Apr;37(4):403–408. [PubMed]
  • Narod SA, Parry DM, Parboosingh J, Lenoir GM, Ruttledge M, Fischer G, Eldridge R, Martuza RL, Frontali M, Haines J, et al. Neurofibromatosis type 2 appears to be a genetically homogeneous disease. Am J Hum Genet. 1992 Sep;51(3):486–496. [PMC free article] [PubMed]
  • Olschwang S, Tiret A, Laurent-Puig P, Muleris M, Parc R, Thomas G. Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients. Cell. 1993 Dec 3;75(5):959–968. [PubMed]
  • Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet. 1994 Oct 1;52(4):450–461. [PubMed]
  • Parry DM, Kaiser-Kupfer MI, Sherman JL, Pikus A, Eldridge R. Neurofibromatosis 2 (bilateral acoustic or central neurofibromatosis), a treatable cause of deafness. Recommendations for screening and follow-up based on study of one large kindred. Ann N Y Acad Sci. 1991;630:305–307. [PubMed]
  • Ragge NK, Baser ME, Klein J, Nechiporuk A, Sainz J, Pulst SM, Riccardi VM. Ocular abnormalities in neurofibromatosis 2. Am J Ophthalmol. 1995 Nov;120(5):634–641. [PubMed]
  • Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature. 1993 Jun 10;363(6429):515–521. [PubMed]
  • Rouleau GA, Wertelecki W, Haines JL, Hobbs WJ, Trofatter JA, Seizinger BR, Martuza RL, Superneau DW, Conneally PM, Gusella JF. Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature. 1987 Sep 17;329(6136):246–248. [PubMed]
  • Ruttledge MH, Narod SA, Dumanski JP, Parry DM, Eldridge R, Wertelecki W, Parboosingh J, Faucher MC, Lenoir GM, Collins VP, et al. Presymptomatic diagnosis for neurofibromatosis 2 with chromosome 22 markers. Neurology. 1993 Sep;43(9):1753–1760. [PubMed]
  • Sainz J, Figueroa K, Baser ME, Mautner VF, Pulst SM. High frequency of nonsense mutations in the NF2 gene caused by C to T transitions in five CGA codons. Hum Mol Genet. 1995 Jan;4(1):137–139. [PubMed]
  • Sanson M, Marineau C, Desmaze C, Lutchman M, Ruttledge M, Baron C, Narod S, Delattre O, Lenoir G, Thomas G, et al. Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus. Hum Mol Genet. 1993 Aug;2(8):1215–1220. [PubMed]
  • Sato N, Funayama N, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. A gene family consisting of ezrin, radixin and moesin. Its specific localization at actin filament/plasma membrane association sites. J Cell Sci. 1992 Sep;103(Pt 1):131–143. [PubMed]
  • Schachat AP, Shields JA, Fine SL, Sanborn GE, Weingeist TA, Valenzuela RE, Brucker AJ. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology. 1984 Dec;91(12):1609–1615. [PubMed]
  • Sivalingam A, Augsburger J, Perilongo G, Zimmerman R, Barabas G. Combined hamartoma of the retina and retinal pigment epithelium in a patient with neurofibromatosis type 2. J Pediatr Ophthalmol Strabismus. 1991 Nov-Dec;28(6):320–322. [PubMed]
  • Thomas PK, King RH, Chiang TR, Scaravilli F, Sharma AK, Downie AW. Neurofibromatous neuropathy. Muscle Nerve. 1990 Feb;13(2):93–101. [PubMed]
  • Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993 Mar 12;72(5):791–800. [PubMed]
  • Twist EC, Ruttledge MH, Rousseau M, Sanson M, Papi L, Merel P, Delattre O, Thomas G, Rouleau GA. The neurofibromatosis type 2 gene is inactivated in schwannomas. Hum Mol Genet. 1994 Jan;3(1):147–151. [PubMed]
  • van Heyningen V. Genetics. One gene--four syndromes. Nature. 1994 Jan 27;367(6461):319–320. [PubMed]
  • Watson CJ, Gaunt L, Evans G, Patel K, Harris R, Strachan T. A disease-associated germline deletion maps the type 2 neurofibromatosis (NF2) gene between the Ewing sarcoma region and the leukaemia inhibitory factor locus. Hum Mol Genet. 1993 Jun;2(6):701–704. [PubMed]
  • Young DF, Eldridge R, Gardner WJ. Bilateral acoustic neuroma in a large kindred. JAMA. 1970 Oct 12;214(2):347–353. [PubMed]

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

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • OMIM
    OMIM
    OMIM record citing PubMed
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...