The primary objective was to enhance molecular studies in retinitis pigmentosa (RP) such as: DNA linkage analyses, fine mapping, isolation and analysis of Retinitis Pigmentosa genes, the isolation of candidate genes for retinal diseases, screening for microdeletions of syndromic and non-syndromic cases and elucidation of the gene function.
The primary objective of the reseach is to investigate, at the molecular level, the genetic defects that lead to the various forms of retinitis pigmentosa (RP). This includes screening for microdeletions in syndromic and non-syndromic cases, identifying, mapping, isolating, and analysing RP genes, and elucidating their function. One collaborating team from Ireland located the gene for autosomal dominant retinitis pigmentosa (ADRP) on chromosome number 3q, thus triggering the detection of the first point mutations in the rhodopsin molecule. Now, a number of different point mutations are known in ADRP and the technique can be used for clinical purposes such as differential diagnosis, early detection and heterozygote testing in any European RP patient. Very recently, a second gene for ADRP has been located on chromosome 6p by the same Irish center. One collaborating team from The Netherlands has isolated the tapetochoroidal dystrophy (TCD) gene. In the area of gyrate atrophy, an attempt is being made to identify undiagnosed cases among 2000 members of RP societies within the framework of a German pilot study. A team from Sardinia was able to collect a highly promising (probably inbred) material on ADRP, and deoxyribonucleic acids (DNA) from transformed blood cells are currently used for gene localisation studies in other countries. One collaborating group from France has succeeded in locating a gene for retinitis pigmentosa plus congenital hearing loss (Usher Syndrom Type I).
Collaborative investigations have been carried out in European countries into the molecular genetics of retinitis pigmentosa (RP) diseases. Results are as follows:
the gene for choroideremia (TCD) was isolated and sequenced for point mutations;
the gene for autosomal dominant retinitis pigmentosa (ADRP) was localized on chromosome 3q and provided the basis for the subsequent detection of the first rhodopsin mutation in the United States;
molecular technology for screening for point mutations in ADRP has been introduced to participating laboratories and the mutation spectrum of a large number of European patients showed differences from that of the American population;
a cluster of families segregating 4 autosomal recessive retinitis pigmentosa (ARRP) was ascertained and deoxyribonucleic acid (DNA) from blood samples is being used collaboratively for mapping in ARRP;
genes have been identified for Usher Syndrome type I and Norrie Syndrome;
use of linked DNA markers and probes detecting deletions allowed early diagnosis including predictive testing of a number of RP types;
information has been disseminated to researchers, doctors and patient organizations.
Definition of Retinitis Pigmentosa (RP): RP is a general term used to refer to a large group of progressive eye-disorders, primarily involving the retina. RP can be present at birth (congenital RP), it is most often diagnosed in childhood or early adulthood, most affected are legally blind by the age of 40. Macular degeneration is the leading cause of legal blindness in adults over 60. Leber's congenital amaurosis and Stargardt's disease are of infantile and juvenile onset, respectively. Usher syndrome is the leading cause of combined (congenital) deafness and (juvenile onset) progressive blindness. In addition to classical RP and allied retinopathies (eg gyrate atrophy, choroideremia), many RP-syndromes (>50) exist in which pleiotropic genes involve specific progressive pathologies of the central nervous system (eg dementia cerebellar ataxia), deafness, renal disease, and others.
Improved ascertainment and improved assessment of informative patients are prerequisites for proper molecular studies in RP: Although the inherited retinal dystrophies comprise a large variety of specific entities, genetically informative cases for molecular studies may be rare and constitute the limiting factor for scientific progress. The proposed ascertainment programme was therefore based on a double strategy: (a) ophthalmologists, eye-clinics, institutions for the blind and (b) registries and media of RP-patient organisations. Improved assessment of patients entering genetic studies is urgently needed using advanced ophthalmological methods, because a number of genetically different RP-types cannot be distinguished on clinical grounds as of yet. For this purpose a Common European Protocol for ophthalmological investigations was proposed within the programme of the Concerted Action as well as the instalment of the European Information Service on complex RP-syndromes.