Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

4-5 Genomic and transcriptomic analysis of the VPS13A gene in a Mexican American population sample
E. K. Moses, K. A. Freed, M. P. Johnson, T. Dyer, H. H. Göring, J. Charlesworth, J. Curran, M. Carless, and J. Blangero
Dept. of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA

We are using genome wide transcriptional profiles in lymphocytes from more than 1200 Mexican Americans in ~40 large families to assist us in a variety of projects aimed at identifying risk factors for common human disease. We have also recently demonstrated the utility of this dataset to study monogenic disease using cystinosis as an example. All known causal mutations for cystinosis have been found in the CTNS gene coding for the lysosomal cystine transporter cystinosin. We have used CTNS mRNA levels in lymphocytes as a quantitative trait and performed variance components based linkage analysis in our Mexican American families to identify potential regulatory loci. We found (and confirmed) strong evidence for cis-acting regulation and identified a putative trans-acting QTL on chromosome 9q. The VPS13A gene at this QTL is a strong candidate for the trans-acting factor as its mRNA expression in lymphocytes was negatively genetically correlated with CTNS expression levels. We are currently attempting siRNA knockdown in lymphoblastoid cell lines from our families to confirm a trans-acting role for VPS13A on CTNS mRNA expression.
Given the known involvement of VPS13A in chorea-acanthocytosis we have now used our datasets to look for potential trans-acting regulators of VPS13A mRNA expression. We have used a high density SNP dataset for 600 of our Mexican American individuals (genotyped for >500,000 SNP markers), in combination with our lymphocyte expression data for VPS13A in the same individuals, to perform a genome wide association scan. Our strongest associations are for SNPs within the PVRL3 (rs873132; p = 1.53 x 10-6), DRD5 (rs7685513; p = 3.84 x 10-6) and PARD3 (rs7904348; p = 4.37 x 10-6) genes on chromosomes 3, 4, and 10 respectively. Interestingly, the PVRL3 and PARD3 genes code for known interacting proteins. It may also be possible to confirm a trans-acting role for these genes using siRNA knockdown in our lymphoblastoid cell lines.
We have recently re-sequenced ~ 2kb of the proximal promoter of VPS13A in 189 founder individuals from our Mexican American families. We identified 16 SNPs (6 novel), that along with 262 known SNPs in this gene, have now been genotyped in our Mexican American families. Of the 278 SNPs that we successfully genotyped, 50 show strong association with VPS13A mRNA expression levels (i.e., cis-effects) and of the best 5 cis-acting SNPs, 3 SNPs showed significant association with CTNS mRNA expression levels (i.e., trans effects). We are currently analysing this genotype data in combination with our lymphocyte transcriptome data, to identify by association genes downstream of VPS13A. These genes may provide greater insight into the pathophysiology of chorea-acanthocytosis.