Sequence variant in the laminin γ1 (LAMC1) gene associated with familial pelvic organ prolapse

Abstract

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.

Changes in connective tissue in patients with pelvic organ prolapse—a review of the current literature

“…However, also nulliparous women without any risk factors may develop POP. Therefore, a genetic predisposition may play a role as well [6][7][8]. When a mother has POP, the relative risk for the daughter of developing POP is 3.2.…”

Distribution and immunoexpression of LOX, PCP and Myofi broblasts in Vaginal Tissue of Postmenopausal Women with and without Pelvic Organ Prolapse

“…Many of the recognized risk factors that lead to the appearance of POP are not always identifi ed in the group of patients suffering from it, therefore leading us to hypothesize the existence of a genetic predisposition or other factors arising from the connective tissue [4][5][6][7][8][9][10]. The later consists of elastin and collagen fi bers, components that play a vital role in the support mechanism of the tissues [13].…”

“…On the other hand prolapse in nulliparous individuals as well as in patients with none of the aforementioned risk factors may lead us to speculate that there might be a genetic background to its apperence [6][7][8]. This speculation can be further supported by the higher incidence of prolapse in women whose mother (3.2 times higher) or sister (2.4 times higher) presented this condition [9].…”

Genetics and the lower urinary tract

“…Matrix metalloproteinases (MMPs) have been observed to be increased in patients with pelvic floor disorders including prolapse and incontinence 8 (Zong, 2005) Other recent candidate gene studies have focused on genes related to skeletal muscle myosin, 9 p27/kip1, 10 and the basement membrane protein laminin LAMC1. 11 Several groups are currently exploring these possibilities looking for SNPs in larger groups of patients with UI.…”