Ruttledge M H, Andermann A A, Phelan C M, Claudio J O, Han F Y, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi V M, Weksberg R, Kitamura K, Bradburn J M, Hall B D, Propping P, Rouleau G A
Centre for Research in Neuroscience, Montreal General Hospital Research Institute, Canada.
Am J Hum Genet. 1996 Aug;59(2):331-42.
The gene predisposing to neurofibromatosis type 2 (NF2) on human chromosome 22 has revealed a wide variety of different mutations in NF2 individuals. These patients display a marked variability in clinical presentation, ranging from very severe disease with numerous tumors at a young age to a relatively mild condition much later in life. To investigate whether this phenotypic heterogeneity is determined by the type of mutation in NF2, we have collected clinical information on 111 NF2 cases from 73 different families on whom we have performed mutation screening in this gene. Sixty-seven individuals (56.2%) from 41 of these kindreds revealed 36 different putative disease-causing mutations. These include 26 proposed protein-truncating alterations (frameshift deletions/insertions and nonsense mutations), 6 splice-site mutations, 2 missense mutations, 1 base substitution in the 3' UTR of the NF2 cDNA, and a single 3-bp in-frame insertion. Seventeen of these mutations are novel, whereas the remaining 19 have been described previously in other NF2 individuals or sporadic tumors. When individuals harboring protein-truncating mutations are compared with cases with single codon alterations, a significant correlation (P < .001) with clinical outcome is observed. Twenty-four of 28 patients with mutations that cause premature truncation of the NF2 protein, schwannomin, present with severe phenotypes. In contrast, all 16 cases from three families with mutations that affect only a single amino acid have mild NF2. These data provide conclusive evidence that a phenotype/genotype correlation exists for certain NF2 mutations.
人类22号染色体上的2型神经纤维瘤病（NF2）致病基因在NF2患者中呈现出多种多样的不同突变。这些患者的临床表现具有显著差异，从年轻时就患有大量肿瘤的非常严重的疾病到生命后期相对较轻的病症不等。为了研究这种表型异质性是否由NF2中的突变类型所决定，我们收集了来自73个不同家庭的111例NF2病例的临床信息，并对该基因进行了突变筛查。这些家族中的41个家族的67名个体（56.2%）发现了36种不同的假定致病突变。其中包括26种推测的蛋白质截短改变（移码缺失/插入和无义突变）、6种剪接位点突变、2种错义突变、1种NF2 cDNA 3'UTR中的碱基替换以及1个3碱基的框内插入。这些突变中有17种是新发现的，其余19种先前已在其他NF2个体或散发性肿瘤中描述过。当将携带蛋白质截短突变的个体与单密码子改变的病例进行比较时，观察到与临床结果存在显著相关性（P <.001）。28例因突变导致NF2蛋白（雪旺瘤蛋白）过早截短的患者中有24例表现出严重的表型。相比之下，来自三个家族的所有16例仅影响单个氨基酸的突变病例均患有轻度NF2。这些数据提供了确凿的证据，表明某些NF2突变存在表型/基因型相关性。
