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

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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.

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Authors and Affiliations

  1. Department of Human Genetics, University of California, 695 Charles Young Drive South, Gonda Room 5506, Los Angeles, CA, 90095-7088, USA

    Ganka Nikolova, Hane Lee, Suzanne Berkovitz, Stanley Nelson, Janet Sinsheimer & Eric Vilain

  2. Department of Biomathematics, University of California, Los Angeles, CA, USA

    Janet Sinsheimer

  3. Department of Pediatrics, University of California, Los Angeles, CA, USA

    Eric Vilain

  4. Department of Urology, University of California, Los Angeles, CA, USA

    Eric Vilain & Larissa V. Rodríguez

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  1. Ganka Nikolova
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  2. Hane Lee
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  3. Suzanne Berkovitz
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  4. Stanley Nelson
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  5. Janet Sinsheimer
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  6. Eric Vilain
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  7. Larissa V. Rodríguez
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Correspondence to Eric Vilain.

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Eric Vilain, and Larissa V. Rodríguez wish to indicate that they contributed equally to this work and should be considered co-last authors.

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Nikolova, G., Lee, H., Berkovitz, S. et al. Sequence variant in the laminin γ1 (LAMC1) gene associated with familial pelvic organ prolapse. Hum Genet 120, 847–856 (2007). https://doi.org/10.1007/s00439-006-0267-1

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