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为什么单亲二倍体导致的普拉德-威利综合征不存在二倍体过量效应?

Why is there no diploid overdose effect in Prader-Willi syndrome due to uniparental disomy?

作者信息

Smith A

机构信息

Cytogenetics Unit, Children's Hospital, Camperdown, Australia.

出版信息

Acta Genet Med Gemellol (Roma). 1996;45(1-2):179-89. doi: 10.1017/s0001566000001288.

Abstract

Due to DNA technology, it is now apparent that the mechanisms of genetic disease are more complex than the model of a gene with biallelic expression in the diploid state. If a gene is imprinted, monoallelic expression is the norm when the chromosomes of a pair are inherited normally from each parent. Uniparental disomy (UPD) is the abnormal situation where both chromosomes of a pair come from the same parent. When the chromosome contains an imprinted gene, UPD may result in nullisomy or disomy for a functional copy of that gene. If there are two imprinted loci on the same chromosome, UPD for that chromosome results in nullisomy for one imprinted gene but functional disomy for the other a "diploid overdose" (DO). This situation has been well demonstrated in the Prader-Willi syndrome (PWS) which is the nullisomic phenotype for the PWS gene(s) on chromosome 15q11-13. Chromosome 15q11-13 also contains the gene for Angelman syndrome (AS) which has a phenotype distinct from PWS. Both loci are subject to imprinting--in PWS, the imprint is on the maternal chromosome 15, in AS it is on the paternal chromosome 15. All individuals with PWS due to maternal UPD, while functionally nullisomic for the PWS locus, are functionally disomic for the AS locus--a DO situation. Assuming that biallelic expression of an imprinted gene is harmful, one would expect DO for an imprinted gene to produce a phenotypic effect. Cases of PWS due to UPD do not appear to differ from those due to deletion (hypopigmentation in deletional cases can be explained by loss of D15S12 downstream from the critical region). There is no good evidence of DO for the AS locus in PWS due to UPD. Why then was it 'necessary' in evolutionary terms to imprint the AS locus and maintain the imprint faithfully for life. A similar situation of two imprinted genes on the same chromosome occurs with IGF2 and H19 on chromosome 11p15. Maternal imprinting for IGF2 and paternal imprinting for H19 is the norm. Paternal UPD in this situation does lead to a DO effect, namely Beckwith-Wiedemann syndrome. The possibility of a DO effect needs to be considered when assessing the phenotypic spectrum of UPD for other chromosomes currently under investigation.

摘要

由于DNA技术,现在很明显,遗传疾病的机制比二倍体状态下具有双等位基因表达的基因模型更为复杂。如果一个基因被印记,当一对染色体正常地从每个亲本遗传时,单等位基因表达是常态。单亲二体性(UPD)是一种异常情况,即一对染色体都来自同一个亲本。当染色体包含一个印记基因时,UPD可能导致该基因功能拷贝的缺体或双体。如果在同一染色体上有两个印记位点,该染色体的UPD会导致一个印记基因缺体,但另一个印记基因功能双体——“二倍体过量”(DO)。这种情况在普拉德-威利综合征(PWS)中得到了很好的证明,它是15号染色体长臂11-13区PWS基因的缺体表型。15号染色体长臂11-13区还包含天使综合征(AS)的基因,其表型与PWS不同。这两个位点都受到印记——在PWS中,印记在母源15号染色体上,在AS中,印记在父源15号染色体上。所有因母源UPD导致的PWS个体,虽然在功能上对PWS位点是缺体,但对AS位点是功能双体——一种DO情况。假设印记基因的双等位基因表达是有害的,那么人们会预期印记基因的DO会产生表型效应。因UPD导致的PWS病例似乎与因缺失导致的病例没有差异(缺失病例中的色素减退可以通过关键区域下游的D15S12缺失来解释)。没有充分的证据表明因UPD导致的PWS中AS位点存在DO。那么从进化的角度来看,为什么有必要对AS位点进行印记并终生忠实地维持这种印记呢?11号染色体短臂15区的胰岛素样生长因子2(IGF2)和H19也存在同一染色体上两个印记基因的类似情况。IGF2的母源印记和H19的父源印记是常态。在这种情况下,父源UPD确实会导致DO效应,即贝克威思-维德曼综合征。在评估目前正在研究的其他染色体的UPD表型谱时,需要考虑DO效应的可能性。

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