PDF(Sci-hub)
Abstract：
Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous autosomal recessive disorder characterized by an almost total lack of adipose tissue in the body. Mutations in the AGPAT2, BSCL2, CAV1 and PTRF genes define I-IV subtype of BSLC respectively and clinical data indicate that new causative genes remain to be discovered. Here, we retrieved 341 cases from 60 BSCL-related studies worldwide and aimed to explore genotype-phenotype correlations based on mutations of AGPAT2 and BSCL2 genes from 251 cases. We also inferred new candidate genes for BSCL through protein-protein interaction and phenotype-similarity.
Analysis results show that BSCL type II with earlier age of onset of diabetes mellitus, higher risk to suffer from premature death and mental retardation, is a more severe disorder than BSCL type I, but BSCL type I patients are more likely to have bone cysts. In BSCL type I, females are at higher risk of developing diabetes mellitus and acanthosis nigricans than males, while in BSCL type II, males suffer from diabetes mellitus earlier than females. In addition, some significant correlations among BSCL-related phenotypes were identified. New candidate genes prediction through protein-protein interaction and phenotype-similarity was conducted and we found that CAV3, EBP, SNAP29, HK1, CHRM3, OBSL1 and DNAJC13 genes could be the pathogenic factors for BSCL. Particularly, CAV3 and EBP could be high-priority candidate genes contributing to pathogenesis of BSCL.
Our study largely enhances the current knowledge of phenotypic and genotypic heterogeneity of BSCL and promotes the more comprehensive understanding of pathogenic mechanisms for BSCL.
Analysis results show that BSCL type II with earlier age of onset of diabetes mellitus, higher risk to suffer from premature death and mental retardation, is a more severe disorder than BSCL type I, but BSCL type I patients are more likely to have bone cysts. In BSCL type I, females are at higher risk of developing diabetes mellitus and acanthosis nigricans than males, while in BSCL type II, males suffer from diabetes mellitus earlier than females. In addition, some significant correlations among BSCL-related phenotypes were identified. New candidate genes prediction through protein-protein interaction and phenotype-similarity was conducted and we found that CAV3, EBP, SNAP29, HK1, CHRM3, OBSL1 and DNAJC13 genes could be the pathogenic factors for BSCL. Particularly, CAV3 and EBP could be high-priority candidate genes contributing to pathogenesis of BSCL.
Our study largely enhances the current knowledge of phenotypic and genotypic heterogeneity of BSCL and promotes the more comprehensive understanding of pathogenic mechanisms for BSCL.
摘要：
Berardinelli-Seip先天性脂肪营养不良（BSCL）是一种异质性常染色体隐性遗传疾病，其特征是体内几乎完全缺乏脂肪组织。AGPAT2，BSCL2，CAV1和PTRF基因的突变分别定义了BSLC的I-IV亚型，临床数据表明新的致病基因仍有待发现。这里,我们从全球60项BSCL相关研究中检索了341例病例,旨在从251例病例中基于AGPAT2和BSCL2基因突变探讨基因型-表型相关性.我们还通过蛋白质-蛋白质相互作用和表型相似性推断了BSCL的新候选基因。
分析结果表明，II型BSCL与糖尿病发病年龄较早，过早死亡和智力低下的风险更高，是一种比I型BSCL更严重的疾病，但BSCLⅠ型患者更可能有骨囊肿.在I型BSCL中,女性患糖尿病和黑棘皮病的风险高于男性，而在BSCLII型中，男性患糖尿病的时间比女性早。此外,确定了BSCL相关表型之间的一些显著相关性.通过蛋白质-蛋白质相互作用和表型相似性进行新的候选基因预测，我们发现CAV3，EBP，SNAP29、HK1、CHRM3、OBSL1和DNAJC13基因能够是BSCL的致病因子。特别是,CAV3和EBP可能是导致BSCL发病的优先候选基因。
我们的研究在很大程度上增强了目前对BSCL表型和基因型异质性的认识，并促进了对BSCL致病机制的更全面理解。
分析结果表明，II型BSCL与糖尿病发病年龄较早，过早死亡和智力低下的风险更高，是一种比I型BSCL更严重的疾病，但BSCLⅠ型患者更可能有骨囊肿.在I型BSCL中,女性患糖尿病和黑棘皮病的风险高于男性，而在BSCLII型中，男性患糖尿病的时间比女性早。此外,确定了BSCL相关表型之间的一些显著相关性.通过蛋白质-蛋白质相互作用和表型相似性进行新的候选基因预测，我们发现CAV3，EBP，SNAP29、HK1、CHRM3、OBSL1和DNAJC13基因能够是BSCL的致病因子。特别是,CAV3和EBP可能是导致BSCL发病的优先候选基因。
我们的研究在很大程度上增强了目前对BSCL表型和基因型异质性的认识，并促进了对BSCL致病机制的更全面理解。
