Mutations in NALP12 cause hereditary periodic fever syndromes
Mutations in NALP12 cause hereditary periodic fever syndromes
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DOI：
10.1073/pnas.0708616105
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发表时间：
2008-02-05
影响因子：
11.1
通讯作者：
Amselem, S.
中科院分区：
文献类型：
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作者：
Jeru, I.;Duquesnoy, P.;Amselem, S.
NALP蛋白，也称为NLRP，属于CATERPILLER蛋白家族，与Toll样受体一样，参与微生物分子的识别以及随后的炎症和免疫应答的激活。NALP功能的当前进展支持最近提出的疾病连续体桥接自身免疫性和自身炎症性疾病的模型。在这些疾病中，遗传性周期性发热（HPFs）是与极少数基因的序列变异相关的孟德尔疾病;这些变异大多是错义突变，其有害影响特别难以评估，通常是值得怀疑的。由于发现的周期性发热综合征散发病例越来越多，加上缺乏区别性的临床标准，大大妨碍了发现新的致病基因，而这一步对于适当管理这些疾病至关重要。使用候选基因方法，我们鉴定了NALP 12中的非模糊突变（即，无义和剪接位点）在两个家庭与周期性发热综合征。如通过功能研究所示，这两个NALP 12突变对NF-κ B信号传导具有有害影响。总的来说，这些数据确定了一组由NALP 12中的分子缺陷定义的HPF，开辟了管理这些疾病的新方法。在患有自身炎症性疾病的患者中鉴定这些第一NALP 12突变也清楚地证明了NALP 12在炎症信号传导途径中的关键作用，从而将精确的功能分配给新兴蛋白质家族的这个特定成员，其推定的生物学特性目前基本上通过体外手段推断。
NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12(i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappa B signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.