The ARC syndrome is a rare autosomal recessive disorder, which refers to an association between Arthrogryposis, Renal tubular dysfunction and Cholestasis.
Approximately 40 patients have been reported since the association was first described in 1973, but cases may go undiagnosed as not all patients present with the three major features. Additional symptoms are reported in patients with the ARC syndrome as well and clinical presentation shows a remarkable variability, even within the same families. So far, the genetic basis for ARC syndrome remains unknown.
The aim of this project is to identify the disease locus responsible for the ARC syndrome and finally to clone the mutated gene.
Currently, we are at the stage of trying to find the disease locus. We are doing this by homozygosity mapping in a few consanguineous families. This method is based on searching for two identical copies of a disease locus inherited from a common ancestor, also called homozygosity by descent (HBD) (figure 1).
To find such a HBD disease locus, microsatellite markers are used. These markers are recognizable di-, tri- or tetranucleotide genomic repeats which can differ in size between individuals, enabling us to determine the haplotypes of the different patients. Because patients with ARC syndrome, originating from a consanguineous family, will have the same haplotype in the region of the disease locus, in this region there will be no variation in size of the markers between the two alleles of these patients.
This method will increase the power of our approach to find the disease locus.
At the moment the following Research-physician is working on this project: Janneke Stapelbroek
Publication:
Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, McKiernan PJ, Klomp LW, Morris AA, Wraith JE, McClean P, Lynch SA, Thompson RJ, Lo B, Quarrell OW, Di Rocco M, Trembath RC, Mandel H, Wali S, Karet FE, Knisely AS, Houwen RH, Kelly DA, Maher ER. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet. 2004 Apr;36(4):400-4. Epub 2004 Mar 28.
Latest update: 30 May 2005