T he p h e n o ty p e s th at are a s s o c ia te d w ith m u ta tio n s in the peripherin-R D S gene can be grouped into four broad categories. The largest group of mutations appear to m anifest their effect in the peripheral retina and are associated with a RP phenotype of night blindness, visual field constriction and retinal pigm entation. In c o n tra st, the second group o f m utations are a sso c iated with phenotypes that affect primarily or solely the central retina. This in c l u d e s p h e n o ty p e s th a t m a n if e s te d e x c l u s i v e l y in c o n e photoreceptors and those that also later affect rod cells as well. M u tatio n s asso ciated with these first two groups are generally (21/22) point mutations or small deletions in the large intradiscal loop (see figure 5.2). The third phenotypic group is know n as digenic RP and is associated with only three point m utations, two of w h ich are ou tsid e the intradiscal loop. T h ese have been o b serv ed in sp o ra d ic/rec essiv e type RP fam ilie s as co m p o u n d heterozygotes with mutations in the R O M l gene. This gene codes for a protein that exhibits a strong sim ilarity to peripherin-R D S both in its sequence and in tissue distribution and it is known to interact with the peripherin-RDS protein (Bascom, et al., 1992).
5.6.1 The Putative Effect of SSBInsTACT
The p h e n o ty p e in the fam ily with the 6 5 8 in sT A C T m u tatio n described in this study, falls into the fourth phenotypic category, com prising mild conditions that appear to be m ost sim ilar to that found in the r d s m ouse. They are c h a ra c te rise d by abnorm al accum ulation of extracellular material primarily in the m acular at the level of the retinal pigm ent epithelium , often with minim al p h o to recep to r dysfunction. Despite the m ild phenotype the m ode
of inheritance is clearly dom inant in all cases. O ther exam ples w o u ld be the m is s e n s e c h a n g e s A s p l 5 7 A s n , G l y l 6 7 A s p , A r g l 7 2 G l y and A rg 2 2 0 G ln in the in tra d is c a l loop and the
nonsense mutations Tyr258Ter, 313delTG and 1137delTG. The r d s
m ouse m u tatio n is caused by in sertio n of a 9.2kb rep e titiv e e le m e n t in to ex o n 2 g e n e r a tin g a t e r m in a tio n c o d o n in approxim ately the same place in the m olecule as is with 658in TA C T . There is some evidence to suggest that the m utant r d s
protein is not stably translated and represents a null allele (Ma, e t al., 1995). The rds mouse has enlarged phagosomes in the retinal p ig m e n t e p ith e liu m c o n ta in in g large a m o u n ts o f shed disc m aterial (H aw kins, et at., 1985). Similar material may well be the s o u rc e o f the u n u su a l d e p o s its o b s e r v e d in th e p a tte r n dystrophies. In light of the observations in the r d s m ouse, it is p o ss ib le th at the p h e n o ty p e in this fa m ily re fle c ts h a p lo - insufficiency as a result of a null allele which does not result in a functional protein product. It has also been suggested that a likely result of a premature termination codon is a greatly reduced level of ex p ressio n (M cIntosh et al., 1993), w hilst m utations causing adRP and macular degeneration may result from "gain of function" in an aberrant protein product.
T h e d i s t r ib u t i o n o f a c c u m u la te d m a te ria l v a rie s m a rk e d ly b e tw ee n the various sub-types of p attern d y stro p h y . W h eth er this can be explained by differential activity of a small amount of resid u al p ro tein pro d u ct betw een the p e rip h e ral and m ac u la r region or w hether it reflects factors other than peripherin-R D S m utation is unclear. The increasing realisation that the mode of in h e rita n c e o f p erip h erin -R D S m u ta tio n s may not be sim ply
d o m in an t, as m ost clearly exhibited by the reports of digenic inheritance with R O M l (Jacobson, et al., 1995a; Kajiwara, et al.,
1994a), may suggest that the differences betw een these putative 'null' p h e n o ty p e s may refle ct the genetic b a c k g ro u n d in the fa m ily .
5.6.2 Incidence of Peripherin-RDS Mutations
That only one disease causing mutation was detected in this study m ay in d ic a te th at the level o f m a c u la r d ise ase c au se d by peripherin-RDS mutations is quite low, at around 4%. There are no firm estim ates for the level of incidence in the literature but anecdotal evidence would suggest 4% is broadly in line with other studies. Perhaps sig n ifican tly , the incidence of perip h erin -R D S mutations in adRP also appears to be around 5% or less (Kajiwara,
et al., 1991; Souied, et al., 1995). Of course this is dependent on the m utation detection efficien cy , the h e tero d u p lex m ethod has been estim ated to be at least 60-70% effic ie n t, w hich is not substantially less than other methods currently used.