Causatives genes

RP is characterized by enormous genetic heterogeneity. At least 45 different genes and loci have been identified to cause nonsyndromic RP so far. Most mutations affect rods selectively and, through an unknown pathway, cause apoptotic death of the rod cells (clinically leading to night blindness and substantial defects in the peripheral visual field). Cones are seldom directly affected by the identified mutations, but in many cases they degenerate secondarily to rods (clinically leading to visual field constriction, loss of central vision and complete blindness).

Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Genes associated with RP encode proteins that are involved in phototransduction (the process by which the energy of a photon of light is converted in the photoreceptor cell outer segment into a neuronal signal), the visual cycle (production and recycling of the chromophore of rhodopsin), photoreceptor structure and photoreceptor cell transcription factors. However, the function of many genes associated with RP remains unknown. The involvement of apoptotic and multiple non-apoptotic mechanisms in the pathogenesis of RP has been suggested.

Though most cases of RP are monogenic, the disease is very heterogeneous genetically. Many different genes may cause the same disease, while different mutations in the same gene may cause different diseases. Clinical severity and disease phenotype often differ among individuals with the same mutation, most likely as a result of genetic and/or environmental factors. Genotype/phenotype correlations in RP will have to take into account these complexities.

Most genes for RP cause only a small proportion of cases, except for the rhodopsin gene (RHO), which leads to about 25% of dominant RP, the USH2A gene, which might cause about 20% of recessive RP (including many with Usher syndrome type II), and the RPGR gene that accounts for about 70% of X-linked RP. Altogether, mutations in RHO, USH2A and RPGR genes cause about 30% of all cases of RP.

Inheritance and genetic counseling

The inheritance modes of RP include autosomal dominant (ad), autosomal recessive (ar), X-linked (xl), digenic and mitochondrial patterns. Because of the variation in both the nature of the penetrance and expressivity of the genes coding for RP, ocular manifestations widely vary among the inherited modes and even among members within the same family.

Autosomal recessive RP (arRP) is the most frequently inherited type of RP, accounting for approximately 20-30 % of cases with approximately 25 arRP genes identified so far. Mutations in RPE65, PDE6A and PDE6B cause 2-5 % of arRP cases, while mutations in USH2A, which can also cause Usher syndrome, may account for up to 5% of arRP cases. Autosomal recessive RP occurs when both parents are unaffected carriers of the same defective gene. The chance of a child being affected is one in four.

Autosomal dominant RP (adRP) is the second most frequently inherited type of RP, accounting for approximately 15-20 % of cases. Twenty adRP genes have been identified to date (see Three genes, RHO, RP1 and PRPH2, account for approximately 25-30 %, 5-10 % and 5-10 % of adRP cases, respectively. More than 100 RHO mutations have been reported so far, causing variation within the clinical presentations. In adRP, typically, one of the parents is affected by the disease. The chance is one in two of any given offspring being affected by the disease, if the affected parent has one normal and one defective gene.

X-linked RP (xlRP) is the least frequently inherited type of RP, accounting for 6-10 % of cases. Two genes and two additional loci have been identified to date. Mutations in RPGR (also called RP3) and RP2 are the most common causes of xlRP, accounting for 70-90% and 10-20%, respectively, of the xlRP cases. X-linked recessive RP may occur in offspring in two ways. The father can be affected or mother can be carrier of the defective gene. If the father is affected, all sons will be unaffected and all daughters will be carriers. If the mother is the carrier, one in two sons will be affected and one in two daughters will be carriers. In families with xlRP, males are affected; females carry the genetic trait and usually do not experience serious vision loss. However, they can manifest a milder form of the disease.

Very rare modes of inheritance include digenic and mitochondrial DNA patterns. Digenic RP is caused by the simultaneous presence of a mutation in the PRPH2/RDS gene and a mutation in the ROM1 gene.

Regarding family planning issues, the optimal time for determination of genetic risk is before pregnancy. Prenatal testing and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation(s) has been identified in an affected family member