Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with behavioral abnormalities and sleep disturbance. Most patients have the same approximately 4 Mb interstitial genomic deletion within chromosome 17p11.2. To investigate the molecular bases of the SMS phenotype, we constructed BAC/PAC contigs covering the SMS common deletion interval and its syntenic region on mouse chromosome 11. Comparative genome analysis reveals the absence of all three approximately 200-kb SMS-REP low-copy repeats in the mouse and indicates that the evolution of SMS-REPs was accompanied by transposition of adjacent genes. Physical and genetic map comparisons in humans reveal reduced recombination in both sexes. Moreover, by examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal Smith-Magenis critical region (SMCR) to an approximately 1.1-Mb genomic interval that is syntenic to an approxiamtely 1.0-Mb region in the mouse. Genes within the SMCR and its mouse syntenic region were identified by homology searches and by gene prediction programs, and their gene structures and expression profiles were characterized. In addition to 12 genes previously mapped, we identified 8 new genes and 10 predicted genes in the SMCR. In the mouse syntenic region of the human SMCR, 16 genes and 6 predicted genes were identified. The SMCR is highly conserved between humans and mice, including 19 genes with the same gene order and orientation. Our findings will facilitate both the identification of gene(s) responsible for the SMS phenotype and the engineering of an SMS mouse model.

中文翻译：

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染色体17p11.2和小鼠的同义区域上的精确Smith-Magenis综合征关键缺失区间中的基因。

Smith-Magenis综合征（SMS）是与行为异常和睡眠障碍相关的多发性先天性异常/智力低下综合征。大多数患者在染色体17p11.2内具有大约4 Mb的间质基因组缺失。为了研究SMS表型的分子基础，我们构建了BAC / PAC重叠群，覆盖了小鼠染色体11上的SMS常见缺失区间及其同义区域。比较基因组分析显示，缺少所有三个大约200-kb的SMS-REP低拷贝在小鼠中重复出现，表明SMS-REPs的进化伴随着相邻基因的转座。人类的物理图谱和遗传图谱比较表明，男女双方的重组减少。此外，通过检查SMS病人中异常大小缺失的缺失区域，我们将最小的Smith-Magenis临界区（SMCR）精炼为大约1.1 Mb的基因组间隔，该间隔与小鼠中大约1.0 Mb的区域相同。通过同源搜索和基因预测程序鉴定出SMCR及其小鼠同系区域内的基因，并对其基因结构和表达谱进行了表征。除了先前定位的12个基因外，我们还在SMCR中鉴定了8个新基因和10个预测基因。在人SMCR的小鼠同音区域中，鉴定出16个基因和6个预测基因。SMCR在人与小鼠之间高度保守，包括19个具有相同基因顺序和方向的基因。我们的发现将有助于鉴定负责SMS表型的基因和SMS小鼠模型的工程。