PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome
PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome
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DOI：
10.1016/j.ajhg.2010.10.031
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发表时间：
2010-12-10
影响因子：
9.8
通讯作者：
Garg, Abhimanyu
中科院分区：
文献类型：
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作者：
Agarwal, Anil K.;Xing, Chao;Garg, Abhimanyu
我们对最近报道的来自葡萄牙和墨西哥的两个家系进行了纯合性作图，该家系患有常染色体隐性自身炎症综合征，其特征是关节挛缩、肌肉萎缩、小细胞性贫血和脂膜炎诱导的脂肪营养不良（JMP）。这揭示了两个家族的所有三名受影响个体共有的 6p21 号染色体上仅有一个跨越 2.4 Mb（5818 个 SNP）的纯合区域。我们直接对位于该关键区域的免疫反应相关基因进行了测序，不包括 HLA 复合体基因。我们在两个家系的受影响患者的蛋白酶体亚基β型8 (PSMB8)基因中发现了纯合错义突变c.224C>T (p.Thr75Met)。该突变以常染色体隐性方式分离，在 275 名不相关的种族匹配的健康受试者中未检测到。 PSMB8 编码 20S 免疫蛋白酶体的催化亚基，称为 β 5i。免疫蛋白酶体介导的蛋白水解作用产生由主要组织相容性复合物 (MHC) I 类分子呈现的免疫原性表位。 75 位的苏氨酸高度保守，用甲硫氨酸取代会破坏 PSMB8 的三级结构。与正常淋巴母细胞相比，来自受影响患者的淋巴母细胞表现出由免疫蛋白酶体介导的胰凝乳蛋白酶样蛋白水解活性显着降低。我们得出的结论是，PSMB8 突变导致 JMP 综合征，很可能是通过影响 MHC I 类抗原加工而导致的。
We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive auto-inflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP). This revealed only one homozygous region spanning 2.4 Mb (5818 SNPs) on chromosome 6p21 shared by all three affected individuals from both families. We directly sequenced genes involved in immune response located in this critical region, excluding the HLA complex genes. We found a homozygous missense mutation c.224C>T (p.Thr75Met) in the proteasome subunit, beta-type, 8 (PSMB8) gene in affected patients from both pedigrees. The mutation segregated in an autosomal-recessive fashion and was not detected in 275 unrelated ethnically matched healthy subjects. PSMB8 encodes a catalytic subunit of the 20S immunoproteasomes called beta 5i. Immunoproteasome-mediated proteolysis generates immunogenic epitopes presented by major histocompatibility complex (MHC) class I molecules. Threonine at position 75 is highly conserved and its substitution with methionine disrupts the tertiary structure of PSMB8. As compared to normal lymphoblasts, those from an affected patient showed significantly reduced chymotrypsin-like proteolytic activity mediated by immunoproteasomes. We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing.