title: Sequence variant in the laminin gamma1 (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.
authors.affiliation: Department of Human Genetics, University of California, 695 Charles Young Drive South, Gonda Room 5506, Los Angeles, CA, 90095-7088, USA.
authors.forename: Ganka
authors.initials: G
authors.lastname: Nikolova
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Suzanne
authors.initials: S
authors.lastname: Berkovitz
authors.forename: Stanley
authors.initials: S
authors.lastname: Nelson
authors.forename: Janet
authors.initials: J
authors.lastname: Sinsheimer
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.forename: Larissa V
authors.initials: LV
authors.lastname: Rodríguez
mesh_terms: D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002874:Chromosome Mapping; D015331:Cohort Studies; D004247:DNA / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014596:Uterine Prolapse / Q000235:genetics* / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; D007797:Laminin; C497440:NFIL3 protein, human; C089141:laminin gamma 1; D004247:DNA