Sequence variant in the laminin γ1 (LAMC1) gene associated with familial pelvic organ prolapse
Sequence variant in the laminin γ1 (LAMC1) gene associated with familial pelvic organ prolapse
复制标题
与家族性盆腔器官脱垂相关的层粘蛋白γ1（LAMC1）基因序列变异
DOI：
10.1007/s00439-006-0267-1
复制
发表时间：
2007-01-01
期刊：
影响因子：
5.3
通讯作者：
Rodriguez, Larissa V.
中科院分区：
文献类型：
--
作者：
Nikolova, Ganka;Lee, Hane;Rodriguez, Larissa V.
盆腔器官脱垂是一种常见的疾病，影响了多达三分之一的女性一生。遗传因素被认为约占30%的发病率，是最不为人所知的疾病组成部分。家族病例，特别是那些年轻女性脱垂的病例，对于寻找相关基因尤其有价值。我们最近报道了常染色体显性遗传是最可能的遗传方式，基于脱垂高发家庭的收集。最令人感兴趣的是一个家庭，这个家庭的三代女性亲属在很小的时候就患有脱垂。使用Affymetrix GeneChip Human mapping 10K阵列进行全基因组连锁扫描，鉴定出10个LOD评分为1.5的区域，这是该家族的最大可能。利用RT-PCR分析这些区域内的候选基因在阴道组织中的表达情况。在确认表达的基因中，通过测序和选择单核苷酸多态性（SNP）基因分型进一步评估LAMC1，以确定受影响家庭成员的致病序列变异。我们发现了一个这样的SNP， rs10911193。与该病症分离的罕见T变异体在一般人群中出现的频率为4.9%，在我们家庭队列的先证者中出现的频率为22%。它影响NFIL3的结合位点，NFIL3是一种我们证实在阴道组织中共表达的转录因子。总之，这些数据表明LAMC1启动子的多态性可能会增加对早发性盆腔器官脱垂的易感性。
Pelvic organ prolapse is a common condition, affecting up to a third of women throughout their lifetime. Genetic factors are believed to account for about 30% of the incidence, and are the least understood component of the disorder. Familial cases, particularly those in which prolapse manifests in young women, are especially valuable in the effort to find the genes involved. We recently reported autosomal dominant transmission as the most likely mode of inheritance, based on a collection of families with high incidence of prolapse. Of greatest interest was a family in which three generations of female relatives suffered from prolapse at a very young age. A genome-wide linkage scan performed using the Affymetrix GeneChip Human mapping 10K array identified ten regions with a LOD score of 1.5, the maximum possible for this family. Candidate genes within those regions were analyzed for expression in vaginal tissue by RT-PCR. Of the genes confirmed to be expressed, LAMC1 was further evaluated by sequencing and select single nucleotide polymorphism (SNP) genotyping for causative sequence variants in affected family members. We identified one such SNP, rs10911193. The rare T variant segregating with the condition is present at a frequency of 4.9% in the general population and 22% among probands from our cohort of families. It affects the binding site for NFIL3, a transcription factor that we verified to be co-expressed in vaginal tissue. Altogether these data suggest that a polymorphism in the promoter of LAMC1 may increase the susceptibility to early-onset pelvic organ prolapse.