Identification of a novel death domain-containing adaptor molecule for ectodysplasin-a receptor that is mutated in crinkled mice
Identification of a novel death domain-containing adaptor molecule for ectodysplasin-a receptor that is mutated in crinkled mice
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DOI：
10.1016/s0960-9822(02)00687-5
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发表时间：
2002-03-05
期刊：
影响因子：
9.2
通讯作者：
Dixit, VM
中科院分区：
文献类型：
--
作者：
Yan, MH;Zhang, ZM;Dixit, VM
少水性外胚层发育不良（HED）是一种见于人类和小鼠的遗传性疾病。它的特点是失去头发，汗腺和牙齿。主要的X-连锁形式是由外胚层发育不良-A（EDA）（一种TNF样配体）突变引起的[1-4]。该疾病的表型上不可区分的常染色体形式由EDA受体（EDAR）的突变引起[4，5]。EDAR是TNF受体家族的一种NF-κ B活化、含有死亡结构域的成员[6-8]。在一种小鼠品系中发现了HIED的一种独特的常染色体形式，其中配体（EDA）和受体（EDAR）均为野生型，这表明信号传导途径的下游进一步受到破坏[9，10]。采用正向遗传学方法，我们克隆了crinkled（CR），发现它编码一种新的含死亡结构域的衔接子。crinkled通过同型死亡结构域相互作用结合EDAR，并介导NF-κ B途径的参与，可能是通过将TRAF 2募集到受体信号传导复合物中。这是配体、受体或衔接子中天然发生的突变的前所未有的例子，其引起相同的表型疾病，其特征在于表皮附属物的正常发育缺陷。
Hypohydrotic Ectodermal Dysplasia (HED) is a genetic disease seen in humans and mice. It is characterized by loss of hair, sweat glands, and teeth. The predominant X-linked form results from mutations in ectodysplasin-A (EDA), a TNF-like ligand [1-4]. A phenotypically indistinguishable autosomal form of the disease results from mutations in the receptor for EDA (EDAR) [4, 5]. EDAR is a NF-kappaB-activating, death domain-containing member of the TNF receptor family [6-8]. crinkled, a distinct autosomal form of HIED, was discovered in a mouse strain in which both the ligand (EDA) and receptor (EDAR) were wild-type, suggestive of a disruption further downstream in the signaling pathway [9, 10]. Employing a forward genetic approach, we have cloned crinkled (CR) and find it to encode a novel death domain-containing adaptor. crinkled binds EDAR through a homotypic death domain interaction and mediates engagement of the NF-kappaB pathway, possibly by recruiting TRAF2 to the receptor-signaling complex. This is an unprecedented example of naturally occurring mutations in ligand, receptor, or adaptor giving rise to the same phenotypic disease characterized by a defect in the proper development of epidermal appendages.