Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome.
Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome.
复制标题
DOI：
10.1093/hmg/8.8.1357
复制
发表时间：
1999-08
影响因子：
3.5
通讯作者：
T. Tsai;Yong-hui Jiang;J. Bressler;D. Armstrong;A. Beaudet
中科院分区：
文献类型：
--
作者：
T. Tsai;Yong-hui Jiang;J. Bressler;D. Armstrong;A. Beaudet
普瑞德威利综合征 (PWS) 是由人类染色体 15q11-q13 父系缺陷引起的。关于 SNRPN 直接参与 PWS 的发病机制，来自人类易位的证据相互矛盾，并且尚不清楚表型特征是由单个印记基因还是多个基因的表达缺失引起的。为了剖析小鼠 7C 号染色体同源区域的基因型/表型相关性，我们制备了三种突变基因型：（i）Snrpn 外显子 2 缺失的小鼠，该小鼠删除了小型上游开放阅读框（ORF）的一部分； (ii) 双靶向 Snrpn 外显子 2 和 Ube3a 的小鼠； (iii) 将小鼠从 Snrpn 删除为 Ube3a，删除两个基因座和干预基因的编码外显子。删除 Snrpn 外显子 2 的小鼠没有明显的表型异常，并且该区域的基因组印记转换是保守的。父本染色体上携带 Snrpn - Ube3a 缺失的小鼠在断奶前表现出严重的生长迟缓、肌张力低下和大约 80% 的致死率。幸存的小鼠具有生育能力，并且在 14 个月大时也没有肥胖。该缺失会遗传多代，并且在父系遗传时继续导致部分致死，但在母系遗传时则不会。缺失区域外的基因necdin的正常印记表达和甲基化模式表明该缺失不是印记突变。数据表明，Snrpn 和 Ipw 之间存在父系表达的结构基因，其缺陷会导致致死，但也存在其他可能性，包括对印迹基因表达的位置影响或 Snrpn 的两个 ORF 同时缺陷会导致致死。
Prader-Willi syndrome (PWS) is caused by paternal deficiency of human chromosome 15q11-q13. There is conflicting evidence from human translocations regarding the direct involvement of SNRPN in the pathogenesis of PWS and it is not known if the phenotypic features result from the loss of expression of a single imprinted gene or multiple genes. In an attempt to dissect genotype/phenotype correlations for the homologous region of mouse chromosome 7C, we prepared three mutant genotypes: (i) mice with a deletion of Snrpn exon 2, which removes a portion of a small, upstream open reading frame (ORF); (ii) mice with double targeting for Snrpn exon 2 and Ube3a; (iii) mice deleted from Snrpn to Ube3a, removing coding exons for both loci and intervening genes. Mice deleted for Snrpn exon 2 have no obvious phenotypic abnormalities and switching of the genomic imprint for the region is conserved. Mice carrying the Snrpn - Ube3a deletion on the paternal chromosome showed severe growth retardation, hypotonia and approximately 80% lethality before weaning. The surviving mice were fertile and were not obese up to 14 months of age. The deletion was transmitted for multiple generations and continued to cause partial lethality when inherited paternally, but not when inherited maternally. The normal imprinted expression and methylation patterns of necdin, a gene outside the deletion region, indicate that the deletion is not an imprinting mutation. The data suggest the presence of a paternally expressed structural gene between Snrpn and Ipw whose deficiency causes lethality, although other possibilities exist, including position effects on expression of imprinted genes or that simultaneous deficiency of both ORFs of Snrpn causes lethality.