Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2

Individuals affected with the neurofibromatosis 2 (NF2) cancer predisposition syndrome develop specific ocular lesions. To determine whether these lesions result from altered NF2 gene expression, microdissection and PCR were used to investigate 40 ocular lesions from seven eyes of four NF2 patients for LOH, with markers that flank the NF2 gene on chromosome 22q. NF2 protein (merlin) expression was also evaluated in these lesions, using immunohistochemistry. Retinal hamartoma was observed in all seven eyes, including one with combined pigment epithelial and retinal hamartoma (CPERH). Retinal tufts were present in four eyes (three patients), retinal dysplasia in two eyes (two patients), optic nerve neurofibroma in one eye, iris naevoid hyperplasia in two eyes (two patients) and pseudophakia in all eyes. Markers were informative in three patients (six eyes from three unrelated families). One patient was non‐informative due to prolonged decalcification. All retinal and optic nerve, but not iris lesions, demonstrated consistent LOH for the NF2 gene. Merlin was not expressed in the retina, optic nerve, or iris lesions. These results suggest that inactivation of the NF2 gene is associated with the formation of a variety of retinal and optic nerve lesions in NF2 patients. Copyright © 2002 John Wiley & Sons, Ltd.

[1]  A. Stemmer-Rachamimov,et al.  Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. , 2001, American journal of human genetics.

[2]  J. Kerrison.  Neuro-ophthalmology of the phacomatoses , 2000, Current opinion in ophthalmology.

[3]  M. Stolte,et al.  Gastric polyps: an update of their pathology and biological significance , 2000, Virchows Archiv.

[4]  B. Scheithauer,et al.  Merlin, DAL‐1, and Progesterone Receptor Expression in Clinicopathologic Subsets of Meningioma: A Correlative Immunohistochemical Study of 175 Cases , 2000, Journal of neuropathology and experimental neurology.

[5]  G. Lueder,et al.  Pseudopapilledema in neurofibromatosis type 2. , 2000, American journal of ophthalmology.

[6]  J M Friedman,et al.  NF1 gene and neurofibromatosis 1. , 2000, American journal of epidemiology.

[7]  P. Crino,et al.  New developments in the neurobiology of the tuberous sclerosis complex. , 1999, Neurology.

[8]  M. Brodsky,et al.  Morning glory disc anomaly in neurofibromatosis type 2. , 1999, Archives of ophthalmology.

[9]  A. Vortmeyer,et al.  VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. , 1999, Archives of ophthalmology.

[10]  J. Gusella,et al.  Merlin: the neurofibromatosis 2 tumor suppressor. , 1999, Biochimica et biophysica acta.

[11]  D. Gutmann.  Molecular Insights into Neurofibromatosis 2 , 1997, Neurobiology of Disease.

[12]  B. Korf,et al.  The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. , 1997, JAMA.

[13]  I. Pollack,et al.  Neurofibromatosis 1 and 2 , 1997, Brain pathology.

[14]  V. Riccardi,et al.  The ocular presentation of neurofibromatosis 2 , 1997, Eye.

[15]  G. Rouleau,et al.  Neurofibromatosis type 2: a new mechanism of tumor suppression , 1996, Trends in Neurosciences.

[16]  S. Pulst,et al.  Expression of neurofibromatosis 2 transcript and gene product during mouse fetal development. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[17]  M. Kaiser-Kupfer,et al.  Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. , 1996, American journal of human genetics.

[18]  M. Brodsky,et al.  Blindness, deafness, quadriparesis, and a retinal malformation: the ravages of neurofibromatosis 2. , 1996, Survey of ophthalmology.

[19]  D. Barton,et al.  Molecular genetic investigation of the neurofibromatosis type 2 tumor suppressor gene in sporadic meningioma. , 1996, Journal of Neurosurgery.

[20]  E. Zwarthoff.  Neurofibromatosis and associated tumour suppressor genes. , 1996, Pathology, research and practice.

[21]  S. Pulst,et al.  Ocular abnormalities in neurofibromatosis 2. , 1996, American journal of ophthalmology.

[22]  G. Rouleau,et al.  Widespread but cell type-specific expression of the mouse neurofibromatosis type 2 gene , 1995, Neuroreport.

[23]  A. Rothner,et al.  Retinal changes associated with neurofibromatosis 2. , 1995, Transactions of the American Ophthalmological Society.

[24]  M I Kaiser-Kupfer,et al.  Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. , 1994, American journal of medical genetics.

[25]  M. Sanson,et al.  The neurofibromatosis type 2 gene is inactivated in schwannomas. , 1994, Human molecular genetics.

[26]  N. Ragge,et al.  Clinical and genetic patterns of neurofibromatosis 1 and 2. , 1993, The British journal of ophthalmology.

[27]  K. Landau,et al.  Ocular fundus in neurofibromatosis type 2. , 1993, The British journal of ophthalmology.

[28]  S. Pulst,et al.  Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2 , 1993, Nature.

[29]  J. Haines,et al.  A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor , 1993, Cell.

[30]  D. Evans,et al.  A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling. , 1992, Journal of medical genetics.

[31]  G. Beauchamp,et al.  Ocular findings associated with neurofibromatosis type II. , 1992, Ophthalmology.

[32]  M. Kaiser-Kupfer,et al.  FAMILIAL OCCURRENCE OF COMBINED PIGMENT EPITHELIAL AND RETINAL HAMARTOMAS ASSOCIATED WITH NEUROFIBROMATOSIS 2 , 1992, Retina.

[33]  G. Perilongo,et al.  Combined hamartoma of the retina and retinal pigment epithelium in a patient with neurofibromatosis type 2. , 1991, Journal of pediatric ophthalmology and strabismus.

[34]  W. Hoyt,et al.  Bilateral retinal hamartomas in neurofibromatosis type 2. , 1991, The British journal of ophthalmology.

[35]  W. Hoyt,et al.  Retinal hamartoma in neurofibromatosis 2. , 1990, Archives of ophthalmology.

[36]  W. Hoyt,et al.  Optic disk glioma in neurofibromatosis type 2. , 1989, American journal of ophthalmology.

[37]  Manuel B. Datiles III,et al.  The association of posterior capsular lens opacities with bilateral acoustic neuromas in patients with neurofibromatosis type 2. , 1989, Archives of ophthalmology.

[38]  R. Sica,et al.  Type 2 neurofibromatosis with Lisch nodules. , 1989, Neurofibromatosis.

[39]  R. L. Font,et al.  Combined hamartoma of sensory retina and retinal pigment epithelium. , 1989, Retina.

[40]  D. Albert,et al.  Intraocular neurilemmoma arising from the posterior ciliary nerve in neurofibromatosis. Pathologic findings. , 1988, Ophthalmology.

[41]  J. Haines,et al.  Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22 , 1987, Nature.

[42]  M. Kaiser-Kupfer,et al.  Eye findings in bilateral acoustic (central) neurofibromatosis: association with presenile lens opacities and cataracts but absence of Lisch nodules. , 1986, The New England journal of medicine.

[43]  R. Martuza,et al.  Loss of genes on chromosome 22 in tumorigenesis of human acoustic neuroma , 1986, Nature.

[44]  L. Rossant.  [The phakomatoses]. , 1977, L'Infirmiere francaise.

[45]  F. Recklinghausen,et al.  Ueber die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen , 1882 .

[46]  J. Wishart.  Case of Tumours in the Skull, Dura Mater, and Brain , 1822, Edinburgh medical and surgical journal.