What can cell biology tell us about heterogeneity in lysosomal storage diseases?
What can cell biology tell us about heterogeneity in lysosomal storage diseases?
复制标题
DOI：
10.1080/08035320510028210
复制
发表时间：
2005-03-01
期刊：
影响因子：
3.8
通讯作者：
Gieselmann, V
中科院分区：
文献类型：
--
作者：
Gieselmann, V
溶酶体贮积病在发病年龄、症状进展和涉及的特定器官方面具有临床异质性。与导致相应疾病的不同缺陷等位基因相关的不同水平的残留酶活性是造成这种临床异质性的部分原因。一般来说，残余酶活性越高，表型越温和。酶活性在严重形式的疾病往往是零，并在轻度形式通常不超过约5%。然而，这种相关性并不严格到可以预测个体患者的表型。不同水平的酶活性的分子基础只能通过对有缺陷的溶酶体蛋白的生物化学研究来揭示。等位基因可能是由于剪接位点突变或缺失。在错义突变的情况下，酶经常不正确地折叠并保留在内质网中，随后降解。由于这些酶不能到达溶酶体，因此它们不提供任何功能性残余活性。仅在缺陷酶到达溶酶体并保留酶活性的情况下观察到残留酶活性。由于修饰基因和表观遗传因素，携带相同突变等位基因的患者仍表现出相当大的表型变异性。到目前为止，这些都没有得到澄清。然而，有一些迹象表明，剪接因子机制的差异可能会影响剪接位点突变的表型表达和激素调节继发性小胶质细胞活化的溶酶体贮积症也可能影响疾病course.Conclusion：表型变异是一种常见的现象，溶酶体贮积病。残留酶活性已被确定为影响疾病临床结局的因素之一;然而，很明显，其他遗传和表观遗传因素也会影响表型变异性，特别是在晚发型疾病患者中。
Lysosomal storage diseases are clinically heterogeneous with respect to their age of onset, progression of symptoms and the particular organs involved. Varying levels of residual enzyme activity, associated with different defective alleles that cause the respective diseases, are responsible in part for this clinical heterogeneity. In general, the higher the residual enzyme activity, the milder the phenotype. Enzyme activity in severe forms of disease is frequently zero, and in mild forms usually does not exceed approximately 5%. However, the correlation is not so strict as to allow prediction of the phenotype of individual patients. The molecular basis of the different levels of enzyme activity can only be revealed by biochemical investigations of the defective lysosomal proteins. Null alleles may be due to splice-site mutations or deletions. In the case of missense mutations, enzymes frequently fold incorrectly and are retained in the endoplasmic reticulum and subsequently degraded. As these enzymes do not reach the lysosome, they do not provide any functional residual activity. Residual enzyme activity is only observed in cases where the defective enzyme reaches the lysosome and has retained enzymatic activity. Patients carrying the same mutant alleles still show considerable phenotypic variability due to modifying genes and epigenetic factors. None of these has so far been elucidated. However, there are some indications that differences in splicing-factor machinery may influence the phenotypic expression of splice-site mutations and that hormonal modulation of secondary microglial activation in lipidosis may also influence the disease course.Conclusion: Phenotypic variability is a frequent phenomenon in lysosomal storage diseases. Residual enzyme activity has been identified as one of the factors influencing the clinical outcome of disease; however, it is obvious that other genetic and epigenetic factors also affect phenotypic variability, particularly in patients with late onset disease.