Rational diagnostic strategy for Zellweger syndrome spectrum patients
Rational diagnostic strategy for Zellweger syndrome spectrum patients
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DOI：
10.1038/ejhg.2008.252
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发表时间：
2009-06-01
影响因子：
5.2
通讯作者：
Gaertner, Jutta
中科院分区：
文献类型：
--
作者：
Krause, Cindy;Rosewich, Hendrik;Gaertner, Jutta
齐薇格综合征谱 (ZSS) 包括一种临床和遗传异质性疾病实体，由 12 种不同的人类 PEX 基因中的任何一种突变导致过氧化物酶体生物发生受损而引起。通过测量血浆和血清中超长链脂肪酸、降植烷酸和植烷酸水平升高以及红细胞中醚磷脂水平降低，对可能患有 ZSS 的患者进行生化诊断。已发表的关于 ZSS 患者诊断程序的报告仅限于生化标记或 PEX 基因子集中的确定突变。明确受影响患者的主要遗传缺陷对于遗传咨询、携带者检测或产前诊断至关重要。在这项研究中，我们为疑似 ZSS 的患者提出了合理的诊断策略。通过以适当的序列结合细胞生物学和分子遗传学方法，我们能够在足够的时间和成本内检测各种 PEX 基因的潜在突变。我们将这种方法应用于乔治奥古斯特大学儿科和小儿神经病学系的 90 名患者，并在 6 个不同的 PEX 基因内检测到 174 个突变等位基因，包括 PEX6 中的两个新的缺失和三个新的错义突变。此外，该策略将扩展我们对各种 PEX 基因的基因型-表型相关性的了解。它将有助于更好地了解 ZSS 发病机制，从而研究不同突变对 PEX 蛋白与体内过氧化物酶体功能之间相互作用的影响。欧洲人类遗传学杂志 (2009) 17, 741-748; doi：10.1038/ejhg.2008.252； 2009 年 1 月 14 日在线发布
Zellweger syndrome spectrum (ZSS) comprises a clinically and genetically heterogeneous disease entity, which is caused by mutations in any of the 12 different human PEX genes leading to impaired biogenesis of the peroxisome. Patients potentially suffering from ZSS are diagnosed biochemically by measuring elevated levels of very long chain fatty acids, pristanic acid and phytanic acid in plasma and serum and reduced levels of ether phospholipids in erythrocytes. Published reports on diagnostic procedures for ZSS patients are restricted either to biochemical markers or to defined mutations in a subset of PEX genes. Clarification of the primary genetic defect in an affected patient is crucial for genetic counselling, carrier testing or prenatal diagnosis. In this study, we present a rational diagnostic strategy for patients suspected of ZSS. By combining cell biology and molecular genetic methods in an appropriate sequence, we were able to detect the underlying mutation in various PEX genes within adequate time and cost. We applied this method on 90 patients who presented at our institute, Department of Pediatrics and Pediatric Neurology at Georg August University, and detected 174 mutant alleles within six different PEX genes, including two novel deletions and three new missense mutations in PEX6. Furthermore, this strategy will extend our knowledge on genotype-phenotype correlation in various PEX genes. It will contribute to a better understanding of ZSS pathogenesis, allowing the investigation of the effects of diverse mutations on the interaction between PEX proteins and peroxisomal function in vivo. European Journal of Human Genetics (2009) 17, 741-748; doi: 10.1038/ejhg.2008.252; published online 14 January 2009