Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome
Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome
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DOI：
10.1093/hmg/ddl443
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Campion, Dominique
中科院分区：
文献类型：
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作者：
Raux, Gregory;Bumsel, Emilie;Campion, Dominique
22q11区域的微缺失与快速心面综合征（VCFS）有关，与精神病和智力迟钝的风险增加有关。最近，在高脯氨酸血症小鼠模型中显示，位于半缺失区域的两个基因，脯氨酸脱氢酶（PRODH）和儿茶酚-o-甲基转移酶（COMT）之间的相互作用可能参与了这种表型。在这里，我们进一步表征了8名儿童I型高脯氨酸血症（HPI）的分子基础，这是一种由脯氨酸脱氢酶（POX）活性降低引起的隐性疾病。我们表明，这些患者表现出智力迟钝、癫痫，在某些情况下，还表现出精神特征。我们接下来报道，在92名成人或青少年VCFS受试者中，有一部分患有严重高脯氨酸血症的患者具有与其他VCFS患者不同的表型，使人联想到HPI。正向逐步多元回归分析选择高脯氨酸血症、精神病和COMT基因型作为影响整个VCFS样本智商的自变量。血浆脯氨酸水平与智商呈负相关。此外，正如从小鼠模型中预测的那样，携带Met-COMT低活性等位基因的高脯氨酸血症VCFS受试者有精神病风险（OR = 2.8, 95% CI = 1.04-7.4）。最后，通过对PRODH基因编码序列变异的广泛分析，我们预测0-30%范围内的痘残余活性会导致HPI，而30-50%范围内的残余活性与正常血浆脯氨酸水平或轻度至中度高脯氨酸血症有关。
Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.