Sutcliffe J S, Jiang Y H, Galijaard R J, Matsuura T, Fang P, Kubota T, Christian S L, Bressler J, Cattanach B, Ledbetter D H, Beaudet A L
Genome Res. 1997 Apr;7(4):368-77. doi: 10.1101/gr.7.4.368.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct clinical phenotypes resulting from maternal and paternal deficiencies, respectively, in human chromosome 15qll-q13. Although several imprinted, paternally expressed transcripts have been identified within the PWS candidate region, no maternally expressed gene has yet been identified within the AS candidate region. We have developed an integrated physical map spanning the PWS and AS candidate regions and localized two breakpoints, including a cryptic t(14;15) translocation associated with AS and a non-AS 15q deletion, which substantially narrow the AS candidate region to approximately 250 kb. Mapping data indicate that the entire transcriptional unit of the E6-AP ubiquitin-protein ligase (UBE3A) gene lies within the AS region. The UBE3A locus expresses a transcript of approximately 5 kb at low to moderate levels in all tissues tested. The mouse homolog of UBE3A was cloned and sequenced revealing a high degree of conservation at nucleotide and protein levels. Northern and RT-PCR analysis of Ube3a expression in mouse tissues from animals with segmental, paternal uniparental disomy failed to detect substantially reduced or absent expression compared to control animals, failing to provide any evidence for maternal-specific expression from this locus. Recent identification of de novo truncating mutations in UBE3A taken with these observations indicates that mutations in UBE3A can lead to AS and suggests that this locus may encode both imprinted and biallelically expressed products.
安吉尔曼综合征（Angelman syndrome，AS）和普拉德-威利综合征（Prader-Willi syndrome，PWS）是分别由人类染色体15q11-q13上母源和父源缺陷导致的不同临床表型。尽管在普拉德-威利综合征候选区域内已鉴定出几种印记的、父源表达的转录本，但在安吉尔曼综合征候选区域内尚未鉴定出母源表达的基因。我们构建了一个跨越普拉德-威利综合征和安吉尔曼综合征候选区域的综合物理图谱，并定位了两个断点，其中包括一个与安吉尔曼综合征相关的隐匿性t(14;15)易位和一个非安吉尔曼综合征的15q缺失，这将安吉尔曼综合征候选区域大幅缩小至约250 kb。图谱数据表明，E6-AP泛素蛋白连接酶（UBE3A）基因的整个转录单元位于安吉尔曼综合征区域内。UBE3A基因座在所有测试组织中均以低至中等水平表达约5 kb的转录本。克隆并测序了UBE3A的小鼠同源物，结果显示在核苷酸和蛋白质水平上具有高度保守性。对来自具有节段性父源单亲二体的动物的小鼠组织中Ube3a表达进行的Northern和RT-PCR分析表明，与对照动物相比，未检测到表达显著降低或缺失，无法为该基因座的母源特异性表达提供任何证据。结合这些观察结果，最近对UBE3A中从头截断突变的鉴定表明，UBE3A突变可导致安吉尔曼综合征，并提示该基因座可能编码印记和双等位基因表达产物。
