Molecular basis of the craniofacial anomalies in SMS

描述（由申请人提供）：面部畸形是许多畸形综合征的一致特征。对畸形模式和特定面部特征的识别对于在这种遗传条件下建立诊断至关重要。然而，面部畸形的分子基础在很大程度上仍然未知。Smith-Magenis综合征（SMS）具有明显的颅面特征，这是一种微缺失综合征，与p11.2带17号染色体短臂约4mb间质缺失有关。除颅面异常外，临床表现还包括智力低下、行为问题和睡眠障碍。我们已经将负责SMS表型的关键区域（SMCR）细化到大约1.1 Mb的间隔，该间隔在人和小鼠之间高度保守。通过染色体工程，我们产生了包含与人类SMS删除间隔的合成区域相对应的基因缺失的Df（17）小鼠。在这些小鼠中观察到颅面异常。因此，SMS中负责颅面异常的基因已经缩小到一个相对较小的（大约1Mb），对人类和小鼠基因组区域都有明确的定义，完整和注释的基因组序列。本研究旨在鉴定导致SMS颅面缺陷的基因。颅面缺损的机制将通过骨骼和组织学分析的结合进一步研究。我们建议使用小鼠基因组克隆从同步区间到人类SMCR来挽救Df（17）小鼠的表型。这些基因组克隆的基因表达谱将被检测，候选基因将通过基因靶向在小鼠中突变，假设纯合的零等位基因可能比单倍不足的等位基因对颅面发育有更深远的影响。本提案的研究将确定负责SMS面部特征的致病基因。许多这些特征也可以在其他智力迟钝综合症中观察到。此外，我们的研究可能有助于理解正常颅面发育的遗传调控以及与SMS相关的异常发育。

DESCRIPTION (provided by applicant): Facial dysmorphology is a consistent feature of many malformation syndromes. Recognition of dysmorphic patterns and specific facial features can be essential for establishing a diagnosis in such genetic conditions. However, the molecular basis for facial dysmorphology remains largely unknown. Distinct craniofacial features have been described for Smith-Magenis syndrome (SMS), a microdeletion syndrome associated with an ~4 Mb interstitial deletion of the short arm of chromosome 17 in band p11.2. In addition to craniofacial abnormalities, the clinical features include mental retardation, behavioral problems, and sleep disturbance. We have refined the critical region (SMCR) responsible for the SMS phenotype to an approximately 1.1 Mb interval that is highly conserved between humans and mice. By chromosome engineering we have generated Df(17) mice encompassing a genetic deletion corresponding to the syntenic region of the human SMS deleted interval. Craniofacial abnormalities have been observed in those mice. Thus, the gene(s) responsible for craniofacial anomalies in SMS has been narrowed to a relatively small (approximately 1Mb), well defined, complete and annotated genomic sequence for both human and the mouse genomic region. This proposal seeks to identify the genes that cause craniofacial defects in SMS. The mechanisms for craniofacial defects will be studied further by a combination of skeletal and histological analysis. We propose to rescue the phenotype in the Df(17) mice using mouse genomic clones from the interval syntenic to the human SMCR. The expression profiles of genes within these genomic clones will be examined and the candidate genes will be mutated in mice by gene targeting with the hypothesis that homozygous null alleles will likely have a more profound effect on craniofacial development than those resulting from haploinsuffciency. Studies in this proposal will determine the causative genes responsible for the facial features of SMS. Many of these features are also observed in other mental retardation syndromes. Furthermore, our investigations will likely aid in the understanding of the genetic regulation of normal craniofacial development as well as the development of anomalies associated with SMS.