E. M. Bleeker-Wagemakers

Thr4Lys rhodopsin mutation is associated with autosomal dominant retinitis pigmentosa of the cone-rod type in a small Dutch family

A mother and daughter with autosomal dominant retinitis pigmentosa (adRP) were found to carry a cytosine-to-adenine transversion mutation at codon 4 of the rhodopsin gene. This mutation predicts a substitution of lysine for threonine at one of the glycosylation sites in the rhodopsin molecule (Thr4Lys). Both patients presented with a similar phenotype including a tigroid pattern of the posterior pole and a regional predilection for degenerative pigmentary changes in the inferior retina with corresponding visual field defects. The electroretinographic pattern was suggestive of RP of the cone-rod type. This report documents the clinical findings associated with this defined mutation of the rhodopsin gene.

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.

A retrospective study of registered retinitis pigmentosa patients in The Netherlands

A retrospective study was performed of patients with retinitis pigmentosa (RP) registered at the Department of Ophthalmogenetics of the Netherlands Ophthalmic Research Institute. The aim was to establish the relative frequencies of the genetic modes and to attempt a clinical subclassification. Of the 575 RP patients, 10.4% were X-linked, 22.4% autosomal dominant, 30.1% autosomal recessive, and 37.1% simplex cases. Clinical classification was inconclusive, and consequently correlation of phenotype to genotype impossible in most cases. One exception was the occurrence of a tapetal reflex, which seemed to differentiate between RP2 and RP3. Gene defects have not been detected so far in Dutch families with either autosomal dominant or autosomal recessive RP. In the future, simplex cases will have to be classified according to their genetic defects. It is probable that results of DNA studies may prove a better basis for classification of RP than clinical data.

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.