Meechan D W, Maynard T M, Tucker E S, LaMantia A-S
Department of Pharmacology and Physiology and GW Institute for Neuroscience, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street NW, Washington, DC, USA.
Int J Dev Neurosci. 2011 May;29(3):283-94. doi: 10.1016/j.ijdevneu.2010.08.005. Epub 2010 Sep 15.
DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes--particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites--the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes--especially those that influence the cell cycle or mitochondrial function--remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients.
迪乔治综合征，即22q11缺失综合征（22q11DS），是最常见的可存活的人类基因缺失疾病，由人类22号染色体上至少32个连续基因的缺失引起，推测是由于这些基因中的一个、一些或全部剂量减少所致——尤其是在发育过程中。然而，22q11基因在胚胎或新生儿中的正常功能，以及它们对作为22q11DS发病基础的发育发病机制的贡献尚未完全明确。我们的数据表明，大量22q11基因特异性地协同作用，在表型受损部位——四肢、心脏、面部和前脑——介导早期形态发生相互作用和随后的细胞分化。当这些基因中的一大组剂量减少时，早期形态发生会改变，最初的22q11DS表型就会形成。此后，功能相似的22q11基因子集——尤其是那些影响细胞周期或线粒体功能的基因——仍然表达，特别是在发育中的大脑皮层，以调节神经发生和突触发育。当这些基因的剂量减少时，正常行为所必需的神经元和神经回路的数量、位置和连接可能会受到破坏。这种破坏可能导致大多数22q11DS患者易患精神分裂症、自闭症或注意力缺陷/多动障碍。
