Divergent phenotypes in Gaucher disease implicate the role of modifiers
Divergent phenotypes in Gaucher disease implicate the role of modifiers
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DOI：
10.1136/jmg.2004.028019
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发表时间：
2005-06-01
影响因子：
4
通讯作者：
Sidransky, E
中科院分区：
文献类型：
--
作者：
Goker-Alpan, O;Hruska, KS;Sidransky, E
背景资料：戈谢病分为神经病性和非神经病性两种形式，在具有相同基因型的患者中具有广泛的表型变异。虽然常见的L444P等位基因的纯合性通常与neuronopathic的形式，如何定义的基因型导致一个表型仍然unknowed.Methods：遗传和表观遗传因素引起的表型差异进行了探讨的临床关联研究，在32名儿童纯合子的点突变L444P。直接测序和Southern印迹法用于确定基因型并排除重组等位基因。葡萄糖脑苷脂酶活性测定淋巴母细胞和成纤维细胞line.Results：残留酶活性是高度可变的，并没有与观察到的临床过程。也有一个广泛的表型谱。诊断时的平均年龄为15个月，扫视眼球运动减慢是最常见的发现。在酶替代疗法（ERT）出现之前，最严重的全身并发症和最高的死亡率发生在脾切除患者中。在ERT方面，随着发病率和死亡率的下降，发育和语言缺陷成为一个主要问题。一些趋势与种族背景observed.Conclusion：广泛的临床光谱中观察到的L444P纯合子牵连的贡献，遗传修饰定义的表型戈谢病。
Background: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown.Methods: The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines.Results: Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed.Conclusion: The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.