Abstract for presentation at 11th International Congress of Human Genetics

Complex genetic approaches to monogenic disease: Genomic and transcriptomic dissection of normal expression of CTNS, the gene involved in nephropathic cystinosis

  • Dr Eric Moses, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States
  • Dr Joanne Curran, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States
  • Dr Matthew Johnson, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States
  • Dr Shelley Cole, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States
  • Dr Jean MacCluer, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States
  • Dr John Blangero, Southwest Foundation for Biomedical Research, San Antonio, Texas, United States

    • Mutations in the CTNS gene on chromosome 17p13 cause cystinosis, a rare autosomal recessive disease characterized by defective transport of cystine out of lysosomes. While CTNS mutations account for all known cases of cystinosis we hypothesized that there are likely to be other genes involved in the pathogenesis of cystinosis, acting either upstream as regulators of CTNS gene expression or downstream having a more direct involvement in disease pathology. To test this hypothesis we chose to study the biology of the CTNS gene in a large sample of unaffected families based on the assumption that normal human variation in CTNS expression could inform us about the determinants and consequences of this important gene’s function. Specifically we set out to measure the level of expression of the CTNS gene in the peripheral blood lymphocytes of 1004 individuals from 40 large Mexican American families that we have previously genome-scanned. Using the Illumina BeadArray platform, we successfully measured the quantitative expression of over 20,000 gene transcripts, including CTNS. Quantitative genetic analysis revealed that 35% (p = 1.2 × 10-10) of the observed variation in CTNS expression was heritable. A linkage-based genome scan was performed to search for QTLs influencing CTNS gene expression. Of eight putatively linked regions identified, there was strong evidence (LOD = 3.05, p = 8.9 × 10-5) for a locus on chromosome 17 at the exact location of the CTNS gene. This finding strongly points to the existence of cis-acting regulatory variation in or around the CTNS locus. We then interrogated the transcriptional profiles to identify downstream genes whose expression levels are pleiotropically influenced by this CTNS expression QTL. Using this approach, we identified a novel pancreatic enzyme known to be involved in diabetic nephropathy that appears to be jointly regulated by CTNS. This new gene may be responsible for some of the nephropathic symptoms seen in cystinosis.

    Conference Organiser - ICMS Pty Ltd