RP1 and Retinitis Pigmentosa: Report of Novel Mutations and Insight into Mutational Mechanism

Abstract

Purpose: : to identify the molecular basis of Retinal Dystrophies in the Saudi population

Methods: : Familial and single RP cases were enrolled in this study, all of which came from consanguineous families. DNA samples from all affected individuals were genotyped using the Affymetrix Gene Chip Human Mapping 250K Arrays. Genome-wide scan was done using easylinkage Multi-point analysis on familial cases, multiple loci were suggested and evaluation of the potential loci was aided by homozygosity analysis. Direct sequencing of all exons of RP1 was done.

Results: : Four novel mutations were identified in RP1 gene in 5 different consanguineous families, and one sporadic case. Mutations were nonsense (NM_006269.1:c.4552A>T) in family arRP-F028, a homozygous single base deletion (NM_006269.1:c.3428delA) in three families (arRP-F043, arRP-F84, and arRP-DF01), a homozygous frameshift mutation ((NM_006269.1:c.3677_3678dupA) in family arRP-F101, and a homozygous nonsense mutation (NM_006269.1:c.33396G>A) in a sporadic case (sRP-19).All mutations were clustered in exon 4. These mutations were predicted to truncate the RP1 protein by approximately 50% of the full length and make it insensitive to the nonsense-mediated decay pathway, leading to the production of truncated proteins which lacks one-half to two-thirds of the C terminal portion.

Conclusions: : To date approximately 47 truncation mutations have been identified in RP1, all of which are located on exon 4, except for the two recessive mutations in exon 3. Among the truncation mutations in exon4 only two mutations have been implicated in arRP. Here we are reporting four novel mutations to cause arRP which provides supporting evidence that mutations in RP1 can result in arRP. Our findings indicate that truncation of RP1 protein after the position p.1131 within the C terminal result in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or downstream from the double cortin domains may result in a protein with a deleterious effect. Moreover, we propose that the motif downstream of the two DCX domains harbor a critical sequence which is likely affect protein stability, and thus all mutations before this motif result in adRP, yet all the mutations beyond this position are more likely to result in arRP.

Keywords: retinitis • genetics • gene mapping