IDENTIFICATION OF IMPRINTED GENES ON CHROMOSOME 14

单亲二体(UPD)是指来自同一亲本的两个染色体拷贝的异常遗传，而不是来自另一个亲本的特定染色体的贡献。UPD已被描述为许多人类染色体，导致不同的临床结果。异常的表型可能是由于染色体上的基因受到基因组印记的影响。基因组印迹是一种分子机制，通过这种机制，母系或父系遗传的染色体上的基因可以有不同的表达。母亲和父亲的14号染色体二体的临床描述使得能够对每种情况下不同的症状进行描述。父系14二体的个体表现出更多的表型，包括智力低下，导致胸腔狭窄的短肢侏儒症的骨骼异常，由于呼吸困难而导致的存活率降低，畸形相，脊柱侧弯和矮小状态。这项应用提出通过两个特定的目的来识别人类14号染色体上的印记基因。首先，将从母系和父系来源的14号染色体中鉴定差异表达的序列。通过直接分析已知基因、杂交到排列的cDNA过滤器和抑制消减杂交来识别印记基因，比较母系二体14或父系二体14的细胞系的表达序列。其次，将对差异表达序列进行特征分析，以了解基因组印记的分子机制和表型的影响。差异表达的序列将被测序，全长的cDNA将被识别。将对序列进行分析，以确定父母特有的甲基化和表达，以开始了解用于控制印迹过程的分子元件。识别受基因组印记影响的基因将有助于深入了解人类发育正常和异常以及智力低下综合征的基因组印记机制，并可能导致对UPD疾病的诊断和分子理解的进一步进展。

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.