Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome.
Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome.
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DOI：
10.1186/1471-2350-6-18
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发表时间：
2005-05-06
影响因子：
--
通讯作者：
Francke U
中科院分区：
文献类型：
--
作者：
Schüle B;Albalwi M;Northrop E;Francis DI;Rowell M;Slater HR;Gardner RJ;Francke U
Prder-Willi综合征(MIM#176270；PWS)是由于在染色体15q11.2的4Mb区域缺乏父系衍生的多个基因的拷贝或其表达而引起的。已知的机制包括大的缺失、母系单亲二体或涉及印记中心的突变。在已报道的5例在Snrpn内含子2或外显子20/内含子20上有断点聚集的个体中，有5例新生平衡相互易位。为了进一步剖析PWS表型并确定PWS特征的最小临界区，我们研究了一名22岁的男性，他具有较温和的PWS表型和新生易位t(4；15)(q27；q11.2)。我们使用中期FISH来缩小断裂点区域，并通过分子分析在核苷酸水平上定位两条染色体上的断裂点。RT-PCR分析断裂点两侧15号染色体上基因的表达。相关的临床特征包括新生儿低眼压伴喂养困难、性腺功能减退、身材矮小、迟发性肥胖、学习困难、异常的社会行为和明显的疼痛耐受性，以及唾液粘稠和嗜睡症。相对的大头畸形和面部特征不是典型的PWS。易位断裂点是在4q27带的剪接非编码转录本的Snrpn内含子17和内含子10中确定的。交换点的直线和正弦序列可能是易位事件的原因。通过对淋巴母细胞和成纤维细胞的RT-PCR分析，我们发现上游的SNURF/Snrpn外显子和snoRNAs HBII-437和HBII-13有表达，而下游的snoRNAs PWCR1/HBII-85和HBII-438A/B的snoRNAs不表达。作为PWCR1/HBII-85 snoRNA簇的一部分，在人和小鼠之间高度保守，而在小鼠中没有发现HBII-438的拷贝，我们认为PWCR1/HBII-85 snoRNAs可能在PWS表型中发挥重要作用。
Prader-Willi syndrome (MIM #176270; PWS) is caused by lack of the paternally-derived copies, or their expression, of multiple genes in a 4 Mb region on chromosome 15q11.2. Known mechanisms include large deletions, maternal uniparental disomy or mutations involving the imprinting center. De novo balanced reciprocal translocations in 5 reported individuals had breakpoints clustering in SNRPN intron 2 or exon 20/intron 20. To further dissect the PWS phenotype and define the minimal critical region for PWS features, we have studied a 22 year old male with a milder PWS phenotype and a de novo translocation t(4;15)(q27;q11.2). We used metaphase FISH to narrow the breakpoint region and molecular analyses to map the breakpoints on both chromosomes at the nucleotide level. The expression of genes on chromosome 15 on both sides of the breakpoint was determined by RT-PCR analyses. Pertinent clinical features include neonatal hypotonia with feeding difficulties, hypogonadism, short stature, late-onset obesity, learning difficulties, abnormal social behavior and marked tolerance to pain, as well as sticky saliva and narcolepsy. Relative macrocephaly and facial features are not typical for PWS. The translocation breakpoints were identified within SNRPN intron 17 and intron 10 of a spliced non-coding transcript in band 4q27. LINE and SINE sequences at the exchange points may have contributed to the translocation event. By RT-PCR of lymphoblasts and fibroblasts, we find that upstream SNURF/SNRPN exons and snoRNAs HBII-437 and HBII-13 are expressed, but the downstream snoRNAs PWCR1/HBII-85 and HBII-438A/B snoRNAs are not. As part of the PWCR1/HBII-85 snoRNA cluster is highly conserved between human and mice, while no copy of HBII-438 has been found in mouse, we conclude that PWCR1/HBII-85 snoRNAs is likely to play a major role in the PWS- phenotype.
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