HPNS seizure risk: a role for the Golgi-associated retrograde protein complex?

Previous attempts to characterize the genetic contribution to differential risk of developing the HPNS seizure in a mouse model system are extended to additional data and an analytical mode that incorporates the set of linked resources for systems genetics in the GeneNetwork project. A quantitative trait locus (QTL) affecting HPNS seizure phenotype was mapped to a approximately 6 megabase (Mb) gene-rich region of Chr 17 based on the degree of expression covariation among genes in the region of the QTL and genes in the brains of BXD recombinant inbred mice in the same chromosomal region. Use of GeneNetwork's WebQTL analytical modules revealed that among > 220 positional candidate genes, vacuolar protein sorting gene 52 (Vps52) has highest priority. It appears that a single nearly null mutation in a distal region of Vps52 3'UTR (untranslated region) defined by a DNA probe set is associated with > 60% of the seizure risk difference between the high- and low-risk strains DBA/2 and C57BL/6, respectively. Based on the known contribution of the elements of the GARP complex--Vps52, -53 and -54--to motoneuron abnormalities, mutation-depleted Vps52 may be implicated in HPNS seizure risk variation in the mouse and, by gene homology, also with human VPS52.