Gökkurt Seda, Peker Eyüboğlu İrem, Nur Güzel Banu, Mihçi Ercan, Özer Ayşe, Akkiprik Mustafa
Division of Medical Biology and Genetics, Department of Health Sciences, Faculty of Medicine, Marmara University, İstanbul, Turkiye.
Division of Pediatric Genetics, Department of Pediatrics, Faculty of Medicine, Akdeniz University, Antalya, Turkiye.
Turk J Med Sci. 2025 Jan 7;55(1):328-336. doi: 10.55730/1300-0144.5973. eCollection 2025.
BACKGROUND/AIM: The aims of this study are to investigate the genotype-phenotype correlation in Sanfilippo type B (MPS IIIB) patients in terms of bone formation/resorption parameters and to determine the release/inhibition of biomarkers accompanying osteoporosis.
Plasma levels of osteoprotegerin (OPG), matrix metalloproteinases (MMP2 and MMP9), tissue inhibitors of metalloproteinase (TIMP1 and TIMP2) and cathepsin K were examined using the ELISA method for a MPS IIIB patient group and a control group. At the same time, mutations in the NAGLU gene causing the disease were identified by whole exome sequencing, and their correlation with biochemical parameters was investigated.
The enzyme analysis results showed that MMP2, MMP9, TIMP1, and TIMP2 were significantly high in the study group, while cathepsin K was low. OPG levels were similar between the two groups. The genetic analysis of patients with MPS IIIB was performed by sequencing all exons and exon-intron junction regions of the NAGLU gene using a next-generation sequencing (NGS) system. In this way, variations were detected qualitatively with high read depths. The analyses found that only two patients had a previously pathogenically defined alteration. In addition, the impact assessment analyses detected alterations with a modifying effect on protein structure.
The genetic analysis results indicate the need to consider a variation classified as benign in the OMIM database as pathogenic because the variations found in the patients (p.Arg737Gly and p.Trp103Cys) have somehow altered enzyme activity. The mutation p.Trp103Cys, a novel NAGLU gene mutation in the first exon, was detected in one patient; additionally, SIFT and PolyPhen analyses confirmed it as damaging. Further functional analyses of this variation should be conducted to gather more comprehensive information.
背景/目的：本研究旨在从骨形成/吸收参数方面研究黏多糖贮积症ⅢB型（MPS IIIB）患者的基因型-表型相关性，并确定伴随骨质疏松症的生物标志物的释放/抑制情况。
采用酶联免疫吸附测定法（ELISA）检测了一组MPS IIIB患者和一组对照组血浆中骨保护素（OPG）、基质金属蛋白酶（MMP2和MMP9）、金属蛋白酶组织抑制剂（TIMP1和TIMP2）以及组织蛋白酶K的水平。同时，通过全外显子测序鉴定了导致该疾病的NAGLU基因中的突变，并研究了它们与生化参数的相关性。
酶分析结果显示，研究组中MMP2、MMP9、TIMP1和TIMP2显著升高，而组织蛋白酶K降低。两组间OPG水平相似。使用下一代测序（NGS）系统对NAGLU基因的所有外显子和外显子-内含子交界区域进行测序，对MPS IIIB患者进行了基因分析。通过这种方式，以高读取深度定性检测到变异。分析发现只有两名患者有先前确定的致病性改变。此外，影响评估分析检测到对蛋白质结构有修饰作用的改变。
基因分析结果表明，由于患者中发现的变异（p.Arg737Gly和p.Trp103Cys）在某种程度上改变了酶活性，因此需要将在线人类孟德尔遗传数据库（OMIM）中分类为良性的变异视为致病性变异。在一名患者中检测到了突变p.Trp103Cys，这是第一个外显子中的一种新型NAGLU基因突变；此外，筛选信息预测工具（SIFT）和多酚类预测工具（PolyPhen）分析证实其具有损害性。应对这种变异进行进一步的功能分析，以收集更全面的信息。
