IDENTIFICATION OF IMPRINTED GENES ON CHROMOSOME 14

单亲二体性（Uniparent disomy，UPD）是指来自同一个亲本的两个染色体拷贝的异常遗传，而另一个亲本的特定染色体没有贡献。UPD已被描述为许多人类染色体，导致不同的临床结果。异常表型可由染色体上的基因引起，所述基因经受基因组印记。基因组印记是指来自父系或母系遗传染色体的基因差异表达的分子机制。无论是母亲和父亲的二体性14例的临床描述，使每一个不同的综合征的特征。具有父亲二体14的个体呈现出更多的表型，包括智力迟钝、导致具有狭窄胸廓的短肢侏儒症的骨骼异常、由于呼吸困难导致的存活率降低、畸形面容、脊柱侧凸和矮小状态。本申请提出通过两个特异性目的鉴定人类14号染色体上的印记基因。首先，将从母系和父系来源的染色体14中鉴定差异表达的序列。将通过已知基因的直接分析、与阵列cDNA滤器的杂交和抑制消减杂交来比较来自母本二体14或父本二体14的细胞系的表达序列，以鉴定印迹基因。第二，差异表达序列的特点，以了解基因组印记的分子机制和表型的影响。将对差异表达的序列进行测序，并鉴定全长cDNA。将分析序列的亲本特异性甲基化和表达，以开始理解用于控制印迹过程的分子元件。识别基因组印迹的基因将允许洞察基因组印迹在正常和异常的人类发育和精神发育迟滞综合征的机制，并可能导致进一步的进步，在诊断和分子水平上的理解UPD疾病。

Uniparental disomy (UPD) is the abnormal inheritance of both copies of chromosome from the same parent with no contribution of that particular chromosome from the other parent. UPD has been described for many human chromosomes, resulting in varying clinical outcomes. An abnormal phenotype may result from genes on a chromosome that are subject to genomic imprinting. Genomic imprinting is the molecular mechanism by which there can be differential expression of genes from either the maternally-or paternally inherited chromosome. The clinical description of cases with either maternal and paternal disomy 14 has enable the characterization of distinct syndromes for each. Individuals with paternal disomy 14 present with a more several phenotype with includes mental retardation, skeletal abnormalities that result in a short- limb dwarfism with narrow thorax, decreased survival due to respiratory difficulties, dysmorphic facies, scoliosis, and short status. This application proposes to identify imprinted genes on human chromosome 14 through two Specific Aims. First, differentially expressed sequences will be identified from maternally- and paternally-derived chromosomes 14. Expressed sequences from cell lines of either maternal disomy 14 or paternal disomy 14 will be compared through direct analysis of known genes, hybridization to arrayed cDNA filters, and suppression subtraction hybridization to identify imprinted genes. Second, differentially expressed sequences will be characterized in order to understand the molecular mechanism of genomic imprinting and the effects of phenotype. The differentially expressed sequences will be sequenced and full length cDNAs will be identified. Sequences will be analyzed for parent-specific methylation and expression to begin to understand the molecular elements used to control the imprinting process. The identification of genes that are subject to genomic imprinting will allow insight into the mechanisms of genomic imprinting in normal and abnormal human development and mental retardation syndromes and may lead to further advances in the diagnosis and molecular understanding of UPD disorders.