Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of β-galactosidase
Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of β-galactosidase
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DOI：
10.1086/302968
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发表时间：
2000-07-01
影响因子：
9.8
通讯作者：
Callahan, JW
中科院分区：
文献类型：
--
作者：
Hinek, A;Zhang, SQ;Callahan, JW
我们以前已经表明，细胞内运输和细胞外组装成弹性纤维的弹性蛋白原是由67-kD的弹性蛋白结合蛋白相同的酶失活，选择性剪接的β-半乳糖苷酶（S-Gal）的变体。在本研究中，我们研究了皮肤成纤维细胞培养物中的弹性纤维组装，这些成纤维细胞来自患有Morquio B病或GM 1神经节苷脂沉积症的患者，这些患者具有不同的β-半乳糖苷酶基因突变。我们发现，取自成人型GM1-神经节苷脂沉积症患者和婴儿型患者的成纤维细胞，携带β-半乳糖苷酶基因的错义突变-突变导致溶酶体β-半乳糖苷酶缺乏，但不是。在S-Gal组装的正常弹性纤维中。相比之下，两例婴儿GM1-神经节苷脂沉积症的成纤维细胞，携带无义突变的β-半乳糖苷酶基因，以及成纤维细胞的四名患者与Morquio B谁有突变导致缺陷的两种形式的β-半乳糖苷酶，没有组装弹性纤维。我们还证明，来自GM 1神经节苷脂沉积症或Morquio B患者的S-Gal缺陷成纤维细胞可以获得S-Gal蛋白，该蛋白通过与S-Gal cDNA永久性横断的中国仓鼠卵巢细胞共培养产生，从而改善弹性纤维的沉积。本研究提供了一种新的和自然的模型，验证功能的作用，S-半乳糖在弹性蛋白和阐明之间的关联受损的弹性蛋白和发展的结缔组织疾病的患者Morquio B疾病和婴儿形式的GM 1-神经节苷脂沉积症的患者。
We have previously shown that intracellular trafficking and extracellular assembly of tropoelastin into elastic fibers is facilitated by the 67-kD elastin-binding protein identical to an enzymatically inactive, alternatively spliced variant of beta-galactosidase (S-Gal). In the present study, we investigated elastic-fiber assembly in cultures of dermal fibroblasts from patients with either Morquio B disease or GM1-gangliosidosis who bore different mutations of the P-galactosidase gene. We found that fibroblasts taken from patients with an adult form of GM1-gangliosidosis and from patients with an infantile form, carrying a missense mutations in the beta-galactosidase gene-mutations that caused deficiency in lysosomal beta-galactosidase but not. in S-Gal-assembled normal elastic fibers. In contrast, fibroblasts from two cases of infantile GM1-gangliosidosis that bear nonsense mutations of the beta-galactosidase gene, as well as fibroblasts from four patients with Morquio B who had mutations causing deficiency in both forms of beta-galactosidase, did not assemble elastic fibers. We also demonstrated that S-Gal-deficient fibroblasts from patients with either GM1-gangliosidosis or Morquio B can acquire the S-Gal protein, produced by coculturing of Chinese hamster ovary cells permanently transected with S-Gal cDNA, resulting in improved deposition of elastic fibers. The present study provides a novel and natural model validating functional roles of S-Gal in elastogenesis and elucidates an association between impaired elastogenesis and the development of connective-tissue disorders in patients with Morquio B disease and in patients with an infantile form of GM1-gangliosidosis.