Retinitis pigmentosa: genetic mapping in X‐linked and autosomal forms of the disease

Abstract

Retinitis pigmentosa (RP) is an hereditary degenerative disease of the retina and a major cause of visual impairment, prevalence estimates ranging from 1 in 3000 to 1 in 7000. The condition may segregate as an autosomal dominant, autosomal recessive or an X‐linked recessive trait and it may also occur on a sporadic basis in up to 50% of cases. In the autosomal dominant form, close linkage to the DNA marker C17 (D3S47) was recently established in a large family of Irish origin displaying early‐onset disease (McWilliam et al. 1989), multipoint analysis indicating the gene for rhodopsin as a likely candidate (Farrar et al. 1990). In that gene, a C→A transversion in codon 23, resulting in a proline→histidine substitution has now been identified in 17 of 148 unrelated ADRP patients in the United States (Dryja et al. 1990). This mutation is absent however in the original Irish pedigree (it is also absent in 21 other dominant Irish pedigrees, representing approximately 70% of the estimated ADRP population) indicating that another mutation, either in rhodopsin itself, or in a gene very closely linked to rhodopsin is responsible for the disease in that family. Analysis of other dominant pedigrees using the C17 and/or rhodopsin probes has indicated either tight linkage (Bhattacharya, Personal Communication), looser linkage, possibly indicative of a second locus on 3q (Olsson et al. 1990) or no linkage (Farrar et al. 1990, Blanton et al. 1990, Inglehearn et al. 1990). Extensive genetic heterogeneity thus exists in the autosomal dominant form of this disease, and in the light of these new observations, earlier tentative evidence for linkage of ADRP to the Rhesus locus on chromosome I will be re‐evaluated. A locus for type II Usher syndrome (classical RP combined with congenital pedial deafness, and normal vestibular function) has now been established on the long arm of chromosome 1 (Kimberling et al. 1990). Type I Usher families, in which hearing loss is more profound and vestibular function absent, do not segregate with the same chromosome 1q markers, indicating the existence of another, as yet unlocated gene. In the X‐linked form of the disease, two genes, XLRP2 and XLRP3, have been located on the proximal short arm of the X chromosome using a combination of physical and linkage mapping techniques, and there is some evidence to suggest a possible third locus more distally located. Advances thus being made, in the localization, isolation and characterization of RP‐causing genes, are likely radically to extend our knowledge of the molecular pathology of this prevalent group of conditions over the next few years.

The rules of variation: Amino acid exchange according to the rotating circular genetic code

“…Examples of some non-conservative changes that break the rules of variation and may end with diseases are Gly–Arg (Armstrong et al, 1996), Pro–Leu and Ala–Glu (Shin et al, 2000), Gly–Asp, causing cystic fibrosis (Hamosh et al, 1992), Gly–Val (Chiu et al, 1993), Glu–Val, causing sickle cell anemia (Serjeant and Serjeant, 1972), Val–Phe (Stafforini et al, 1996), Arg–Gln (Larsen et al, 1998), Glu–Ala (Sluyter et al, 2004), Ser–Cys (Chen et al, 2001), Ser–Pro (Chen et al, 1992), Arg–Pro (Sheppard et al, 1993), Pro–His (Humphries et al, 1990), His–Pro (Dalla-Venezia et al, 1993), His–Tyr (Dear et al, 2004), Tyr–Ala (Lucio and Mazzoni, 2008), Leu–Pro (Belsham et al, 1995), Val–Cys (Saito et al, 2000), and Phe–Cys (Mundo et al, 2001). …”

A qualitative self-study of Retinitis Pigmentosa

“…One such incurable eye disease is Retinitis Pigmentosa (RP), a retinal dystrophy, that has an incidence of one in 3700 in the United States (Margalit and Sadda, 2003), and between one in 3000 and one in 7000 world-wide (Humphries et al, 1990).…”

Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa

“…Prevalence of nonsyndromic RP is approximately 1 in 4000. The condition may segregate as an autosomal dominant, autosomal recessive, or an X-linked recessive trait [Humphries et al, 1990]. All genes identified to date are believed to account for roughly 50% of all retinal dystrophy cases [Pomares et al, 2007].…”