Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels
Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels
复制标题
印度刺猬突变导致 A1 型短指，在多个层面损害刺猬信号转导
DOI：
10.1038/cr.2011.76
复制
发表时间：
2011-09-01
期刊：
影响因子：
44.1
通讯作者：
He, Lin
中科院分区：
文献类型：
--
作者：
Ma, Gang;Yu, Jiang;He, Lin
短指A1型(BDA1)是人类第一个记录的孟德尔常染色体显性遗传病，其特征是中节指骨缩短或缺失。印度刺猬(IHH)基因杂合错义突变已被确认为BDA1的原因之一；然而，这些突变的生化后果尚不清楚。在本文中，我们分析了印度刺猬(IhhN)N端片段中的三个BDA1突变(E95K、D100E和E131K)。结构分析表明，E95K突变将钙结合沟中的负电区改变为正电区，D100E突变改变了局部三级结构。此外，我们发现E95K和D100E突变导致IhhN对温度敏感和钙依赖的不稳定性，这可能有助于通过溶酶体促进突变蛋白在细胞内的降解。值得注意的是，这三个突变都影响了HH与Patched1受体(PTC1)的结合，降低了其诱导细胞分化的能力。我们认为这些是导致BDA1的突变的共同特征，影响HH三级结构，细胞内命运，与受体/伴侣结合，以及与细胞外成分结合。这些特征的组合改变了信号容量和范围，但影响可能是可变的和依赖于突变的。E95K突变的IHH与硫酸乙酰肝素的相互作用增强，而不是E131K突变，这是信号范围的潜在变化。综上所述，我们的结果表明，这些IHH突变在多个水平上影响HH信号，导致骨骼发育异常和手指形成异常。
Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.