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。识别畸形模式和特定的面部特征对于在这种遗传条件下建立诊断是必不可少的。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）是一种与17号染色体p11.2带短臂~4 Mb间质性缺失相关的微缺失综合征，有独特的颅面特征。除了颅面畸形外，临床特征还包括精神发育迟滞、行为问题和睡眠障碍。我们已经改进了负责SMS表型的关键区域（SMCR），使其在人和小鼠之间高度保守，间隔约为1.1 Mb。通过染色体工程，我们已经产生了Df（17）小鼠，其包含与人SMS缺失区间的同线区相对应的遗传缺失。在这些小鼠中观察到颅面异常。因此，负责SMS颅面异常的基因已经缩小到相对较小（约1 Mb），明确定义，完整和注释的人类和小鼠基因组区域的基因组序列。这项提案旨在确定导致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。我们建议使用来自人类SMCR同线区间的小鼠基因组克隆来拯救Df（17）小鼠的表型。将检查这些基因组克隆中基因的表达谱，并通过基因靶向在小鼠中突变候选基因，假设纯合无效等位基因可能对颅面发育产生比单倍体不足引起的影响更深远的影响。这项建议的研究将确定负责SMS面部特征的致病基因。许多这些特征也在其他精神发育迟滞综合征中观察到。此外，我们的研究将可能有助于了解正常颅面发育的遗传调控以及与SMS相关的异常的发展。

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.