S. van Soest

Integrated genetic and physical map of the 1q31-->q32.1 region, encompassing the RP12 locus, the F13B and HF1 genes, and the EEF1AL11 and RPL30 pseudogenes.

The gene for autosomal recessive retinitis pigmentosa (RP12) with preserved para-arteriolar retinal pigment epithelium was previously mapped close to the F13B gene in region 1q31→q32.1. A 4-Mb yeast artificial chromosome contig spanning this interval was constructed to facilitate cloning of the RP12 gene. The contig comprises 25 sequence-tagged sites, polymorphic markers, and single-copy probes, including five newly obtained probes. The contig orders the F13B and HF1 genes, as well as five expressed sequence tags, with respect to the integrated genetic map of this region. Homozygosity mapping resulted in refinement of the candidate gene locus for RP12 to a 1.3-cM region. Currently, approximately 1 Mb of the contig is represented in P1-derived artificial chromosome (PAC) clones. Direct screening of a cDNA library derived from neural retina with PACs resulted in identification of the human elongation factor 1α pseudogene (EEF1AL11) and a human ribosomal protein L30 pseudogene (RPL30). A physical and genetic map covering the entire RP12 candidate gene region was constructed.

Fine mapping of the autosomal recessive retinitis pigmentosa locus (RP12) on chromosome 1q; exclusion of the phosducin gene (PDC)

In a previous study on a large pedigree from a genetically isolated population in the Netherlands, we localized a gene for autosomal recessive retinitis pigmentosa with paraarteriolar preservation of the retinal pigment epithelium (PPRPE) on the long arm of chromosome 1. In this study, we present an integrated genetic map of the target region. The resulting genetic order of the markers was used to construct haplotypes and to screen for key-recombinants in the pedigree. The obligate RP12 region was reduced from 16 cM to 5 cM between the markers D1S533 and CACNL1A3. The CACNL1A3 and phosducin (PDC) genes were placed outside the candidate gene region, thereby excluding the involvement of these genes in retinitis pigmentosa with PPRPE. Our data result in the following order of the markers and genes in the region 1q31 --> q32.1: cen-D1S158-(D1S238-D1S422)/PDC- D1S533-RP12/(F13B-D1S413)-CACNL1A3-DIS4 77-D1S306-D1S53-tel.

Protein tyrosine phosphatase receptor type C polypeptide (PTPRC) on human chromosome band 1q31→q32 localizes with marker D1S4131 on a 610-kb yeast artificial chromosome

PTPRC, formerly known as CD45 and Leukocyte Common Antigen, is a protein tyrosine phosphatase which regulates activation of leukocytes. It has been mapped to a region of chromosome 1q31→q32 within the RCA (regulator of complement activation) gene cluster centromeric to REN and telomeric to F13B (Pardo-Manuel de Villena et al., 1996). Disease linkage with PTPRC has not been defined although a point mutation in exon 4 causes aberrant splicing of isoforms in 8% of the population (Schwinzer et al., 1992) and a patient with abnormal PTPRC expression and immunodeficiency has been reported (Cale et al., 1997). Refining the site of the PTPRC locus on the physical map would be useful for its exclusion or inclusion as a candidate gene in disease associations and in chromosome deletions or amplifications. We report that the 120-kb PTPRC gene co-localizes with marker D1S413 on a 610-kb YAC and therefore considerably refines the previous physical localization of this gene on chromosome 1q31→q32. Materials and methods

3233 Fine mapping of the autosomal recessive retinitis pigmentosa locus (RP12) on chromosome IQ; exclusion of the phosducin gene

m Seven loci for dominant retinitis pigmentoeehave been described in the literature. These include the Rhodopsin and Rdslperipherin genee. and anonymous loci identtfted only by linkage on 7p, 7q. aq, 17p and 19q. We wishedto estimatethe frequendesof the anonymous loci, and determinewhether any adRP loci remained to be found. &@g& DNAe were colleded from twenty ftve adRP families. These were tested by linkage analyeis and mutetiin screening to determine the origin of the phenotype in each family. j&t& Of the twenty five families, the diiease in twelve wes found to be rhcdwein RP either bv linkaae analwie or by mutation detection. A further three map& the 19q adRP &us. one to {he 7p l&us. and one to the 17p locus. Three other familiee gave tentative evidence of linkege,hvo to 19q and one to sq. Four families show crcssovere at all the known loci. Finally in one large family we discovered a new locus. on chromosome 17q between markers D17SBo9 and Dl7S942. Multipoint enalysie in this fern@ gave e maximum led sccfe of 8.24 in this interval. Concluelone In this sample, Rho-RP accounted for approximately50% of adRP while the 19q lccus(RP11) accented for around 20%. All other loci ere rare. Approximately 15% of families map to an unknown locus or loci, proving that adRP is caused by mutations in at least nine dinerent genes.