Saito T, Guan F, Papolos D F, Lau S, Klein M, Fann C S, Lachman H M
Department of Psychiatry, Division of Psychiatry Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Mol Psychiatry. 2001 Jul;6(4):387-95. doi: 10.1038/sj.mp.4000871.
Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2, a chromosomal region that has been linked to BPD in a subset of families in several studies. Synaptojanin 1 is an inositol 5-phosphatase that has an important role in synaptic vesicle endocytosis. Mutation screening of 32 exons, intron--exon junctions, and 839 bases of 5'-flanking DNA resulted in the identification of 11 mutations of which four were very common and seven were very rare. Of the 11 mutations identified, several may have functional significance including two coding variants, two that may affect the binding of a transcription factor, and two that involve known splicing regulatory domains. Five bipolar patients out of 149 analyzed were found who have one of the four rare variants that were most likely to have functional significance compared with 0/148 controls. The allele frequencies for three of the four common variants were very similar in bipolar patients and controls. A slight difference in allele frequency was found for an interesting mutation we detected in intron 12 in which two non-adjacent thymidine residues are deleted in a poly-AT tract located near the exon 12 splice donor site (chi(2) = 2.45, P = 0.12, 2-tailed). Although we failed to unequivocally identify a specific SYNJ1 allele that could be responsible for putative chromosome 21q22-linked BPD, several interesting variants were found to be increased in bipolar subjects and should be further investigated.
参与调节突触小泡功能的基因是精神疾病发生发展的潜在候选基因。除了实验和理论方面的考虑外，一些参与突触小泡功能的基因定位于基因组中与双相情感障碍（BPD）和精神分裂症（SZ）相关的区域。其中一个是突触素1（SYNJ1），它定位于21q22.2，在多项研究的部分家族中，该染色体区域与BPD相关。突触素1是一种肌醇5-磷酸酶，在突触小泡内吞作用中起重要作用。对32个外显子、内含子-外显子连接区以及5'侧翼DNA的839个碱基进行突变筛查，共鉴定出11个突变，其中4个非常常见，7个非常罕见。在鉴定出的11个突变中，有几个可能具有功能意义，包括两个编码变体、两个可能影响转录因子结合的变体以及两个涉及已知剪接调节域的变体。在149名接受分析的双相情感障碍患者中，发现有5名患者携带4种最有可能具有功能意义的罕见变体之一；而对照组的148名患者中无人携带。4种常见变体中的3种在双相情感障碍患者和对照组中的等位基因频率非常相似。我们在第12内含子中检测到一个有趣的突变，该突变在外显子12剪接受体位点附近的一个多聚AT序列中缺失了两个不相邻的胸腺嘧啶残基，双相情感障碍患者和对照组在该突变的等位基因频率上存在轻微差异（卡方检验=2.45，P = = 0.12，双侧）。尽管我们未能明确鉴定出一个可能导致假定的21q22染色体相关BPD的特定SYNJ1等位基因，但发现双相情感障碍患者中几种有趣的变体有所增加，应进一步研究。
