Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations
Novel HAX1 mutations in patients with severe congenital neutropenia reveal isoform-dependent genotype-phenotype associations
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DOI：
10.1182/blood-2007-11-120667
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发表时间：
2008-05-15
期刊：
影响因子：
20.3
通讯作者：
Klein, Christoph
中科院分区：
文献类型：
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作者：
Germeshausen, Manuela;Grudzien, Magda;Klein, Christoph
HAX 1的纯合子突变导致一种常染色体隐性形式的重度先天性中性粒细胞减少症（CN）。通过筛选88例CN患者，我们确定了另外6例携带4种新突变的HAX 1突变患者。其中，2个影响HAX 1的两种已发表的转录变体;其他2个突变仅影响转录变体1。对患者基因型和表型的分析显示了惊人的相关性：仅影响转录变体1的突变与CN相关（23例患者中的23例），而影响两种转录变体的突变导致CN和神经系统症状，包括癫痫和神经发育迟缓（6例患者中的6例）。与外周血相比，转录变体2在人脑组织中显著表达。HAX 1缺陷的临床表型似乎取决于突变的定位及其对转录变体的影响。因此，我们的研究结果表明，HAX 1亚型可能在神经元系统中发挥独特的作用。
Homozygous mutations in HAX1 cause an autosomal recessive form of severe congenital neutropenia (CN). By screening 88 patients with CN, we identified 6 additional patients with HAX1 mutations carrying 4 novel mutations. Of these, 2 affect both published transcript variants of HAX1; the other 2 mutations affect only transcript variant 1. Analysis of the patients' genotypes and phenotypes revealed a striking correlation: Mutations affecting transcript variant 1 only were associated with CN (23 of 23 patients), whereas mutations affecting both transcript variants caused CN and neurologic symptoms, including epilepsy and neuro-developmental delay (6 of 6 patients). In contrast to peripheral blood, transcript variant 2 was markedly expressed in human brain tissue. The clinical phenotype of HAX1 deficiency appears to depend on the localization of the mutation and their influence on the transcript variants. Therefore, our findings suggest that HAX1 isoforms may play a distinctive role in the neuronal system.