Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU
Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU
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DOI：
10.1182/blood-2003-07-2531
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发表时间：
2004-04-01
期刊：
影响因子：
20.3
通讯作者：
Saint Basile, GD
中科院分区：
文献类型：
--
作者：
Neven, B;Callebaut, I;Saint Basile, GD
NALP蛋白是最近鉴定的CATERPILLER（CARD，转录增强子，R（嘌呤）结合，pyrin，许多LRR）蛋白家族的成员，被认为在凋亡和炎症信号传导途径中起作用。CIAS 1基因的突变，其编码NALP（含NACHT-、LRR-和PYD蛋白）家族的成员，cryopyrin/NALP 3/PYPAF 1蛋白，主要在吞噬细胞中表达，最近被发现与一系列自身炎症性疾病相关。这些包括慢性婴儿神经性皮肤和关节（CINCA）综合征（也称为脑源性多系统炎性疾病[NOMID]），Muckle-Wells综合征（MWS）和家族性寒冷性荨麻疹（FCU）。我们在此描述了13例CINCA综合征无关患者的7个新突变，并根据迄今为止描述的所有突变鉴定了CIAS 1中的突变热点。我们还提供了基因型/表型相关性的证据。一个三维模型的核苷酸结合结构域（NBD）的cryopyrin表明，这种分子的结构和功能类似的AAA+蛋白家族的ATP酶的成员。根据该模型，大多数已知影响NBD残基的突变聚集在预测参与分子间接触的区域中该结构域的一侧，表明该模型可能具有生物学相关性，并且核苷酸结合、核苷酸水解或蛋白质寡聚化的缺陷可能导致MWS、FCU和CINCA/NOMID疾病中cryopyrin的功能失调。(C)2004年，美国血液学会。
NALP proteins are recently identified members of the CATERPILLER (CARD, transcription enhancer, R(purine)-binding, pyrin, lots of LRR) family of proteins, thought to function in apoptotic and inflammatory signaling pathways. Mutations in the CIAS1 gene, which encodes a member of the NALP (NACHT-, LRR-, and PYD-containing proteins) family, the cryopyrin/NALP3/PYPAF1 protein, expressed primarily in phagocytic cells, were recently found to be associated with a spectrum of autoinflammatory disorders. These include chronic infantile neurologic cutaneous and articular (CINCA) syndrome (also known as neonatal-onset multisystem inflammatory disease [NOMID]), Muckle-Wells syndrome (MWS), and familial cold urticaria (FCU). We describe herein 7 new mutations in 13 unrelated patients with CINCA syndrome and identify mutational hotspots in CIAS1 on the basis of all mutations described to date. We also provide evidence of genotype/phenotype correlations. A 3-dimensional model of the nucleotide-binding domain (NBD) of cryopyrin suggested that this molecule is structurally and functionally similar to members of the AAA+ protein family of ATPases. According to this model, most of the mutations known to affect residues of the NBD are clustered on one side of this domain in a region predicted to participate in intermolecular contacts, suggesting that this model is likely to be biologically relevant and that defects in nucleotide binding, nucleotide hydrolysis, or protein oligomerization may lead to the functional dysregulation of cryopyrin in the MWS, FCU, and CINCA/NOMID disorders. (C) 2004 by The American Society of Hematology.