Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms
Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms
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DOI：
10.1093/hmg/ddw377
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发表时间：
2017-01-01
影响因子：
3.5
通讯作者：
Sakai, Norio
中科院分区：
文献类型：
--
作者：
Kondo, Hidehito;Maksimova, Nadezda;Sakai, Norio
粘多糖沉积症（MPS）是一组分解代谢糖胺聚糖（GAG）的溶酶体酶的遗传缺陷。在这里，我们描述了一种新的MPS样疾病引起的VPS 33 A基因的特定突变。我们确定了几个雅库特患者表现出典型的MPS表现：粗糙的面部特征，骨骼异常，肝脾肿大，呼吸问题，智力低下，尿GAG分泌过多。然而，这些患者不能被酶诊断为MPS。他们的血浆硫酸乙酰肝素（HS，GAG之一）水平极高;是正常参考范围的60倍，是MPS患者的6倍。此外，大多数患者发生心脏、肾脏和造血系统疾病，这些不是传统MPS的典型症状，导致1 - 2岁之间的致死性结局。利用全外显子组和桑格测序，我们确定了13例患者的VPS 33 A基因纯合c.1492 C>T（p.Arg498 Trp）突变。VPS 33 A参与内吞和自噬途径，但鉴定的突变不影响这些途径中的任一个。在患者来源的和VPS 33 A耗尽的细胞中检测到溶酶体过度酸化和HS积累，表明该基因在溶酶体功能中的新作用。因此，我们提出了一种新型的MPS，这不是由酶缺乏引起的。
Mucopolysaccharidoses (MPS) are a group of genetic deficiencies of lysosomal enzymes that catabolize glycosaminoglycans (GAG). Here we describe a novel MPS-like disease caused by a specific mutation in the VPS33A gene. We identified several Yakut patients showing typical manifestations of MPS: coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, mental retardation, and excess secretion of urinary GAG. However, these patients could not be diagnosed enzymatically as MPS. They showed extremely high levels of plasma heparan sulphate (HS, one of GAG); 60 times the normal reference range and 6 times that of MPS patients. Additionally, most patients developed heart, kidney, and hematopoietic disorders, which are not typical symptoms for conventional MPS, leading to a fatal outcome between 1 and 2-years old. Using whole exome and Sanger sequencing, we identified homozygous c.1492C>T (p.Arg498Trp) mutations in the VPS33A gene of 13 patients. VPS33A is involved in endocytic and autophagic pathways, but the identified mutation did not affect either of these pathways. Lysosomal over-acidification and HS accumulation were detected in patient-derived and VPS33A-depleted cells, suggesting a novel role of this gene in lysosomal functions. We hence propose a new type of MPS that is not caused by an enzymatic deficiency.