Metabolic abnormalities in Williams-Beuren syndrome
Metabolic abnormalities in Williams-Beuren syndrome
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DOI：
10.1136/jmedgenet-2014-102713
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发表时间：
2015-04-01
影响因子：
4
通讯作者：
Alberto Perez-Jurado, Luis
中科院分区：
文献类型：
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作者：
Gabriela Palacios-Verdu, Maria;Segura-Puimedon, Maria;Alberto Perez-Jurado, Luis
Williams-Beuren综合征（WBS, OMIM-194050）是一种多系统表现的神经发育障碍，由7q11.23位点1.55-1.83 Mb缺失引起，包括26-28个基因。报告的内分泌和代谢异常包括婴儿期短暂性高钙血症，约30%的儿童出现亚临床甲状腺功能减退，约75%的成人出现糖耐量受损。本研究的目的是进一步研究WBS患者以及几种小鼠模型的代谢改变，以建立潜在的候选基因。研究人员分析了154例WBS患者的代谢参数（每个参数的数据从69例到151例不等），以及几种同源WBS基因座完全或部分缺失的小鼠模型，并寻找致病基因和潜在的修饰因子。结果与对照组相比，WBS患者血浆甘油三酯水平显著降低，胆固醇水平略有下降。18.3%的WBS病例出现高胆红素血症，多为非偶联性，与亚临床甲状腺功能减退和低甘油三酯血症相关，提示有共同的致病机制。MLXIPL的单倍体不足和UGT1A1基因启动子的次形等位基因外显率增加可能是脂质和胆红素改变的基础。其他干扰包括蛋白质和铁水平升高，以及已知的亚临床甲状腺功能减退和葡萄糖耐受不良。我们的研究结果表明，一些未报道的生化改变与7q11.23位点特定基因的单倍不足有关，在WBS中相对常见。这些代谢紊乱的早期诊断、随访和管理可以预防这种疾病的长期并发症。
Background Williams-Beuren syndrome (WBS, OMIM-194050) is a neurodevelopmental disorder with multisystemic manifestations caused by a 1.55-1.83 Mb deletion at 7q11.23 including 26-28 genes. Reported endocrine and metabolic abnormalities include transient hypercalcaemia of infancy, subclinical hypothyroidism in similar to 30% of children and impaired glucose tolerance in similar to 75% of adult individuals. The purpose of this study was to further study metabolic alterations in patients with WBS, as well as in several mouse models, to establish potential candidate genes.Methods We analysed several metabolic parameters in a cohort of 154 individuals with WBS (data available from 69 to 151 cases per parameter), as well as in several mouse models with complete and partial deletions of the orthologous WBS locus, and searched for causative genes and potential modifiers.Results Triglyceride plasma levels were significantly decreased in individuals with WBS while cholesterol levels were slightly decreased compared with controls. Hyperbilirubinemia, mostly unconjugated, was found in 18.3% of WBS cases and correlated with subclinical hypothyroidism and hypotriglyceridemia, suggesting common pathogenic mechanisms. Haploinsufficiency at MLXIPL and increased penetrance for hypomorphic alleles at the UGT1A1 gene promoter might underlie the lipid and bilirubin alterations. Other disturbances included increased protein and iron levels, as well as the known subclinical hypothyroidism and glucose intolerance.Conclusions Our results show that several unreported biochemical alterations, related to haploinsufficiency for specific genes at 7q11.23, are relatively common in WBS. The early diagnosis, follow-up and management of these metabolic disturbances could prevent long-term complications in this disorder.