Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes

Abstract

Neurofibromatosis 2 (NF2) is an autosomal inherited disorder that predisposes carriers to nervous system tumors. To examine genotype-phenotype correlations in NF2, we performed mutation analyses and gadolinium-enhanced magnetic resonance imaging of the head and full spine in 59 unrelated NF2 patients. In patients with vestibular schwannomas (VSs) or identified NF2 mutations, the mild phenotype was defined as < 2 other intracranial tumors and < or = 4 spinal tumors, and the severe phenotype as either > or = 2 other intracranial tumors of > 4 spinal tumors. Nineteen mutations were found in 20 (34%) of the patients and were distributed in 12 of the 17 exons of the NF2 gene, including intron-exon boundaries. Seven mutations were frameshift, six were nonsense, four were splice site, two were missense, and one was a 3-bp in frame deletion. The nonsense mutations included one codon 57 and two codon 262 C-->T transition in CpG dinucleotides. The frameshift and nonsense NF2 mutations occurred primarily in patients with severe phenotypes. The two missense mutations occurred in patients with mild phenotypes, and three of the four splice site mutations occurred in families with both mild and severe phenotypes. Truncating NF2 mutations are usually associated with severe phenotypes, but the association of some mutations with mild and severe phenotypes indicates that NF2 expression is influenced by stochastic, epigenetic, or environmental factors.

The parental origin of new mutations in neurofibromatosis 2

“…Genomic DNA was extracted from peripheral blood leukocytes or from Epstein-Barr virus-transformed lymphoblastoid cell lines, as previously reported [8,13]. Tumor tissue not needed by pathology departments for diagnosis was retrieved from clinically indicated procedures and frozen in liquid nitrogen or dry ice.…”

“…Since the cloning of this gene, a large number of mutations has been found in over 50% of NF2 patients studied by exon scanning of genomic DNA [11][12][13][14][15][16]. Nonsense and frameshift mutations, which are expected to lead to truncated NF2 gene products, account for approximately 65% of all constitutional mutations.…”

Genetic and clinical characteristics of Korean patients with neurofibromatosis type 2

“…These somatic mutations were found only in tumor tissues and not in peripheral lymphocytes. Of the 10 mutations found, 5 (50.0%) were nonsense mutations, 3 (30.0%) were frameshift mutations, and 2 (20.0%) were splicing mutations [12][13][14][15][16][17][18]. Most mutations were private but one mutation, c.586C>T (p.Arg196Ter), was found to recur in 2 families; two frameshift mutations, c.568del (p.Ala190Leufs*19) and c.1160_1161insA, were not previously reported, and were not found in the general population [19][20][21].…”

Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]

“…48 Nonsense and frame-shifting mutations have been associated with severe disease regardless of their positions within the gene. 48 -52 Splice site mutations have been associated with both mild and severe disease 49,51,53 and may be milder if occurring in the 3Ј half of the gene. 54 Missense mutations are usually mild, often causing the mildest form of NF2.…”