Department of Medical Genetics and Cambridge Institute for Medical Research, University of Cambridge, UK.
Department of Clinical Biochemistry and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
Brain. 2018 May 1;141(5):1286-1299. doi: 10.1093/brain/awy034.
Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.
许多遗传性神经疾病在受影响的家族中表现出可变的表达，通常以疾病发病年龄的变化为例。上位效应（即修饰基因对疾病基因的影响）可能是这种变异的基础，但这种上位相互作用的机制基础很少被理解。在这里，我们报告了 SPAST 和连续基因 DPY30 之间的一种新的上位相互作用，该作用修饰遗传性痉挛性截瘫（一种遗传性轴索病）的发病年龄。我们发现，由 SPAST 基因组缺失引起的遗传性痉挛性截瘫患者，其缺失延伸至 DPY30，发病年龄明显更早。我们表明，与编码 SPAST 的蛋白 spastin 一样，DPY30 蛋白控制内体小管分裂、甘露糖 6-磷酸受体从内体向高尔基体的运输以及溶酶体超微结构形态。我们提出，该途径的附加效应解释了这两个基因杂合不足的遗传性痉挛性截瘫患者发病年龄降低的原因。
