Putative association of a mutant ROM1 allele with retinitis pigmentosa

13 páginas, 1 figura, 1 tabla.Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous form of retinal degeneration. Several genes and loci have been shown to be involved in the disease, although each of them only accounts for a few cases. Mutations in the gene encoding ROM1, a rod-specific protein, have been putatively associated with several forms of RP. Here we describe a double-mutant allele of this gene, P60T and T108M, present in two affected sibs and also in two healthy members of a Spanish RP family. The same double-mutant allele was previously considered to be responsible for autosomal dominant RP in one family. We now report data that question the potential pathogenicity of these two ROM1 mutations.This work was supported by Spanish CICYT (SAF93-0479-062-01; SAF96-0329) and the “Federación de Asociaciones de Afectados de Retinosis Pigmentaria del Estado Español” (FAARPE). A. Martínez-Mir and M. Bayés are recipients of fellowships from the “Generalitat de Catalunya” and L. Dain received an R. H. Thalmann fellowship from Universidad de Buenos Aires.Peer reviewe

Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci.

PURPOSE. Mutations in the systemically expressed pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 have recently been associated with autosomal dominant retinitis pigmentosa (adRP). This study was intended to identify mutations in PRPF3, PRPF8, and PRPF31 in 150 Spanish families affected by adRP, to measure the contribution of mutations in these genes to adRP in that population, and to correlate RP phenotype expression with mutations in pre-mRNA splicing-factor genes. METHODS. Denaturing gradient gel electrophoresis (DGGE) and direct genomic sequencing were used to evaluate the complete coding region and flanking intronic sequences of the PRPF31 gene, exon 42 of PRPF8, and exon 11 of PRPF3 for mutations in 150 unrelated index patients with adRP. Ophthalmic and electrophysiological examination of patients with RP and their relatives was performed according to preexisting protocols. RESULTS. Three nonsense mutations caused by insertion and deletion sequences and two missense mutations (Arg2310Gly) and within the stop codon of the PRPF8 gene (TGA3 TTG), were detected in five unrelated heterozygous patients. Three patients were heterozygous carriers of different nonsense mutations in exon 8 of the PRPF31, gene and one Thr494Met mutation was found in exon 11 of the PRPF3 gene. Cosegregation of the mutation in PRPF8 and PRPF3 with adRP was observed. However, two nonsense mutations in PRPF31 causing adRP detected in two families showed asymptomatic carriers. CONCLUSIONS. Nine mutations, six of which are novel, in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31, causing adRP have been identified in the Spanish population. Their contribution to adRP is approximately 5% after correction in relation to mutations found in other genes causing adRP. The patients carrying a mutation in the pre-mRNA splicing-factor PRPF8 gene showed a type 1 diffuse RP. The existence of asymptomatic carriers of the nonsense mutation in the PRPF31 gene suggests incomplete penetrance for these mutations in the families. 1 The genetics of RP is complex, and the disorder may be inherited through an autosomal dominant (adRP), autosomal recessive (arRP), X-linked (XLRP), 2,3 or digenic 4 trait. Mutations within six genes (RHO, peripherin/RDS, RP1, NRL, CRX, and FSCN2) that encode proteins specifically expressed in photoreceptor cells have been reported to cause adRP. From th