Sumegi J, Huang D, Lanyi A, Davis J D, Seemayer T A, Maeda A, Klein G, Seri M, Wakiguchi H, Purtilo D T, Gross T G
Department of Pathology and Microbiology, Center for Human Molecular Genetics, Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.
Blood. 2000 Nov 1;96(9):3118-25.
The purposes of this study were to determine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families-large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP) or in 9 patients with chronic active EBV syndrome. Of 304 symptomatic males in the XLP Registry, 38 had no evidence of EBV infection at first clinical manifestation. When fulminant infectious mononucleosis (FIM) was excluded, there was no statistical difference in the frequency of EBV infectivity in the other XLP phenotypes. Furthermore, there was no difference at age of first clinical manifestation between EBV(+) and EBV(-) males or in survival when patients with FIM were excluded. In conclusion, it was found that mutations in the SH2D1A gene are responsible for XLP but that there is no correlation between genotype and phenotype or outcome. It was also found that though EBV infection often results in FIM, it is unnecessary for the expression of other manifestations of XLP, and it correlates poorly with outcome. These results suggest that unidentified factors, either environmental or genetic (eg, modifier genes), contribute to the pathogenesis of XLP.
本研究的目的是确定X连锁淋巴增殖性疾病（XLP）中SH2D1A基因突变的频率，以及SH2D1A基因突变和EB病毒（EBV）感染在决定XLP患者的表型和预后方面的作用。对XLP登记处的35个家庭进行分析发现，34个家庭中有28种不同的突变——大的基因组缺失（n = 3）、小的基因内缺失（n = 10）、剪接位点（n = 3）、无义（n = 3）和错义（n = 9）突变。在25名男性（所谓的散发性XLP，即EBV感染后具有XLP表型但无XLP家族史的男性）或9名慢性活动性EBV综合征患者中未发现突变。在XLP登记处的304名有症状男性中，38名在首次临床表现时没有EBV感染的证据。当排除暴发性传染性单核细胞增多症（FIM）时，其他XLP表型中EBV感染率没有统计学差异。此外，EBV（+）和EBV（-）男性在首次临床表现的年龄或排除FIM患者后的生存率方面没有差异。总之，发现SH2D1A基因突变是XLP的病因，但基因型与表型或预后之间没有相关性。还发现，虽然EBV感染常导致FIM，但它不是XLP其他表现形式表达所必需的，且与预后的相关性较差。这些结果表明，未确定的环境或遗传因素（如修饰基因）促成了XLP的发病机制。
