Salama Ilan, Hinderlich Stephan, Shlomai Zipora, Eisenberg Iris, Krause Sabine, Yarema Kevin, Argov Zohar, Lochmuller Hanns, Reutter Werner, Dabby Ron, Sadeh Menachem, Ben-Bassat Hannah, Mitrani-Rosenbaum Stella
Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Biochem Biophys Res Commun. 2005 Mar 4;328(1):221-6. doi: 10.1016/j.bbrc.2004.12.157.
Hereditary inclusion body myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, which is caused by mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), the key enzyme in the biosynthetic pathway of sialic acid. In order to investigate the consequences of the mutated GNE enzyme in muscle cells, we have established cell cultures from muscle biopsies carrying either kinase or epimerase mutations. While all myoblasts carrying a mutated GNE gene show a reduction in their epimerase activity, only the cells derived from the patient carrying a homozygous epimerase mutation present also a significant reduction in the overall membrane bound sialic acid. These results indicate that although mutations in each of the two GNE domains result in an impaired enzymatic activity and the same HIBM phenotype, they do not equally affect the overall sialylation of muscle cells. This lack of correlation suggests that the pathological mechanism of the disease may not be linked solely to the well-characterized sialic acid pathway.
遗传性包涵体肌病（HIBM）是一组独特的神经肌肉疾病，其特征为成人起病、缓慢进展的远端和近端肌肉无力，由唾液酸生物合成途径中的关键酶UDP-N-乙酰葡糖胺2-表异构酶/N-乙酰甘露糖胺激酶（GNE）突变引起。为了研究突变的GNE酶在肌肉细胞中的后果，我们从携带激酶或表异构酶突变的肌肉活检组织中建立了细胞培养物。虽然所有携带突变GNE基因的成肌细胞其表异构酶活性均降低，但只有来自携带纯合表异构酶突变患者的细胞其总膜结合唾液酸也显著降低。这些结果表明，尽管GNE两个结构域中的每一个发生突变都会导致酶活性受损和相同的HIBM表型，但它们对肌肉细胞的总唾液酸化影响并不相同。这种缺乏相关性表明该疾病的病理机制可能并非仅与已充分表征的唾液酸途径相关。
