PDF(Pubmed)
Abstract：
BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease.
METHODS: All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient\'s age at genetic analysis, and patient\'s disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing.
RESULTS: Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their \"frameshift\" nature, a small fraction of these variants may act wholly or partly as \"in-frame\" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data.
CONCLUSIONS: This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.
METHODS: All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient\'s age at genetic analysis, and patient\'s disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing.
RESULTS: Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their \"frameshift\" nature, a small fraction of these variants may act wholly or partly as \"in-frame\" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data.
CONCLUSIONS: This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.
摘要：
背景：脂蛋白脂肪酶（LPL）是甘油三酯水解的限速酶。纯合或复合杂合子LPL变异导致常染色体隐性家族性乳糜微粒血症综合征（FCS），而简单杂合LPL变异体则与高甘油三酯血症(HTG)和HTG相关疾病有关.LPL移码编码序列变体通常会导致受影响的等位基因功能完全丧失，从而允许探索不同水平的LPL功能在人类疾病中的影响。
方法：对妊娠HTG相关急性胰腺炎（HTG-AP）或HTG-AP患者的LPL的所有外显子和侧翼内含子区域进行Sanger测序。先前报道的LPL移码编码序列变体从人类基因突变数据库和通过PubMed关键词搜索进行整理。手动评估原始报告的以下信息：变体的接合性状态，变体载体的血浆LPL活性，基因分析的疾病，基因分析时患者的年龄，和患者的疾病史。使用SpliceAI来预测整理的变体对剪接的潜在影响。
结果：确定了两个新的罕见变异体，和53个已知的LPL移码编码序列变体被整理。在提供接合性信息的51种变体中，30个是简单的杂合子，12个是纯合子，9个为复合杂合子。关于其临床和遗传数据对55个变体的仔细评估产生了几个有趣的发现。首先,我们得出的结论是，6-7％的残留LPL功能可以显着延迟FCS的发病年龄，并降低FCS相关综合征的患病率。第二,而绝大多数LPL移码编码序列变异通过其“移码”性质完全破坏基因功能，这些变体中的一小部分可能全部或部分地充当“框架内”变体，导致产生具有一些残余LPL功能的蛋白质产物。第三，我们基于基因型-表型相关性或SpleeAI预测的数据,鉴定了两个可能保留残余功能的LPL移码编码序列变异体.
结论：本研究报告了两种新的LPL变异体，并对LPL移码编码序列变异体的基因型-表型关系产生了新的见解。
方法：对妊娠HTG相关急性胰腺炎（HTG-AP）或HTG-AP患者的LPL的所有外显子和侧翼内含子区域进行Sanger测序。先前报道的LPL移码编码序列变体从人类基因突变数据库和通过PubMed关键词搜索进行整理。手动评估原始报告的以下信息：变体的接合性状态，变体载体的血浆LPL活性，基因分析的疾病，基因分析时患者的年龄，和患者的疾病史。使用SpliceAI来预测整理的变体对剪接的潜在影响。
结果：确定了两个新的罕见变异体，和53个已知的LPL移码编码序列变体被整理。在提供接合性信息的51种变体中，30个是简单的杂合子，12个是纯合子，9个为复合杂合子。关于其临床和遗传数据对55个变体的仔细评估产生了几个有趣的发现。首先,我们得出的结论是，6-7％的残留LPL功能可以显着延迟FCS的发病年龄，并降低FCS相关综合征的患病率。第二,而绝大多数LPL移码编码序列变异通过其“移码”性质完全破坏基因功能，这些变体中的一小部分可能全部或部分地充当“框架内”变体，导致产生具有一些残余LPL功能的蛋白质产物。第三，我们基于基因型-表型相关性或SpleeAI预测的数据,鉴定了两个可能保留残余功能的LPL移码编码序列变异体.
结论：本研究报告了两种新的LPL变异体，并对LPL移码编码序列变异体的基因型-表型关系产生了新的见解。
