Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts
复制标题
DOI：
10.1038/77153
复制
发表时间：
2000-07-01
期刊：
影响因子：
30.8
通讯作者：
Peltonen, L
中科院分区：
文献类型：
--
作者：
Paloneva, J;Kestilä, M;Peltonen, L
多囊性脂膜性骨发育不良伴硬化性白质脑病 (PLOSL; MIM 221770)，也称为 Nasu-Hakola 病，是一种隐性遗传性疾病，其特征是快速进展为早老性痴呆和仅限于手腕和脚踝的骨囊肿的精神病症状组合 (1-3)。 PLOSL 具有全球分布，尽管大多数患者是在芬兰(4) 和日本确诊的。芬兰人中估计的人口患病率为 2x10(-6)（参考文献 2）。我们之前已经在染色体 19q13.1 上的标记 D1951175 和 D195608 之间的所有芬兰疾病等位基因中鉴定了一个共享的 153 kb 祖先单倍型（参考文献 5,6）。在这里，我们通过识别所有芬兰 PLOSL 等位基因中的一个大缺失和一名日本患者中的另一个突变来表征 PLOSL 的分子缺陷，这两个突变都代表编码 TYRO 蛋白酪氨酸激酶结合蛋白 (7)（TYROBP；以前称为 DAP12）的基因的功能丧失突变。 TYROBP 是一种跨膜蛋白，已被认为是自然杀伤 (NK) 细胞中关键的激活信号转导元件 (8)。在 NK 细胞的质膜上，TYROBP 与识别主要组织相容性复合体 (MHC) I 类分子的激活受体结合 (7,9)。在 TYROBP 无效等位基因纯合的 PLOSL 患者中，未检测到 NK 细胞功能异常。
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles(1-3). PLOSL has a global distribution, although most of the patients have been diagnosed in Finland(4) and Japan. with an estimated population prevalence of 2x10(-6) (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D1951175 and D195608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein(7) (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells(8). On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules(7,9). No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP.