Three novel mutations (P215L, T289P, and 3811-2 A?G) in the rhodopsin gene in autosomal dominant retinitis pigmentosa in Spanish families

Martinez-Gimeno, María; Trujillo, M.J.; Lorda, Isabel; Gimenez, Ascension; Calvo, María Teresa; Ayuso, Carmen; Carballo, Miguel

doi:10.1002/1098-1004(200007)16:1<95::aid-humu31>3.0.co;2-0

Cited by 12 publications

(6 citation statements)

References 3 publications

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“…Scotopic and photopic responses on ERG recordings were nearly extinguished. In line with these clinical findings, molecular testing identified a previously described heterozygous pathogenic missense variant (c.644C>T, p.Pro215Leu, Table 1; Table 2) in the RHO gene (NCBI Reference Sequence NM_000539.3) [18]. The 48-year-old father (IV.3) reported dark adaptation problems since childhood and visual field defects starting in his second decade.…”

Section: Resultsmentioning

confidence: 62%

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

Birtel

Gliem

Hess

et al. 2020

Genes

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Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness.

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Section: Resultsmentioning

confidence: 62%

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

Birtel

Gliem

Hess

et al. 2020

Genes

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“…Two cis-acting mutations in the splicing signals of rhodopsin have thus far been reported in adRP Spanish patients, although cis-acting mutations in the splice sites of other recessive genes have also been found (Bernal et al, unpublished results). These mutations reported in the Spanish families are point mutations (g.3811A4G and g.5167G4T) in the 3 0 splice site of intron 2 and intron 4, respectively, of the rhodopsin gene [Reig et al, 1996;Martínez-Gimeno et al, 2000] The mutations manifest as adRP with total penetrance in both families. However, a similar rhodopsin mutation (g.4335G4T) in the 5 0 splice site of intron 4 has been reported as recessive in two different populations [Rosenfeld et al, 1995;Greenberg et al, 2003], with only the homozygous carriers of the mutation exhibiting RP.…”

Section: Discussionmentioning

confidence: 97%

“…Transcriptional Expression of RHO Minigenes With a Cis-Acting Mutation in an Exon/Intron Boundary Splice Site Nearly 15% of adRP in a Spanish population are linked to mutations within the rhodopsin gene, two of which have been identified and linked to aberrant splicing [Reig et al, 1996;Martínez-Gimeno et al, 2000;Millá et al, 2002]. Here, we constructed minigenes containing the two previously identified cis-acting splicing mutations (g.3811A4G and g.5167G4T) in the RHO gene linked to adRP and a third reported mutation g.4335G4T linked to arRP [Rosenfeld et al, 1995;Greenberg et al, 2003] (Supplementary Fig.…”

Section: Screening For Mutations In Genes Associated With Adrpmentioning

confidence: 99%

“…More than 30 different mutations in the rhodopsin gene (MIM] 180380, accession ID U49742.1), accounting for 15% of adRP in a Spanish population, have been identified [Millá et al, 2002]. Two of these mutations, g.3811A4G and g.5167G4T, are singlenucleotide substitutions that affect the splicing signals of the intron 2/exon 3 and intron 4/exon 5 boundaries [Reig et al, 1996;Martínez-Gimeno et al, 2000]. These splicing mutations are associated with complete penetrance of adRP, while a similar type of mutation in the flanking sequences of exon 4 (g.4335G4T) has been found to be recessive [Rosenfeld et al, 1995;Greenberg et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional expression ofcis-acting andtrans-acting splicing mutations cause autosomal dominant retinitis pigmentosa

et al. 2008

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Two types of mutations may lead to deficient pre-mRNA splicing: cis-acting mutations that inactivate a constitutive or alternative splice site within the pre-mRNA, and trans-acting mutations that affect the function of a basal factor of the splicing machinery. Autosomal dominant retinitis pigmentosa (adRP) is caused by mutations in at least 12 genes, with mutations in rhodopsin being the most prevalent. Two cis-acting mutations, g.3811A>G and g.5167G>T at the splice site in the rhodopsin gene (RHO; GenBank U49742.1) are linked to adRP in a Spanish population; while a cis-acting mutation, g.4335G>T, has been linked to recessive RP (arRP). Transcriptional expression analysis showed that the cis-acting splicing mutations linked to adRP promoted alternative splice sites, while the arRP linked mutation results in exclusion of exon 4. Trans-acting splicing mutations associated with adRP have also been found, and mutations in the pre-mRNA splicing factors PRPF3, PRPF8, PRPF31, and RP9 are associated with adRP in several populations. This report describes a new mutation in PRPF3 in a Spanish adRP family. We also investigated the transcriptional patterns in Epstein-Barr virus (EBV)-transformed lymphoblastoid cells from patients carrying a mutation in PRPF8. Despite the role of PRPF8 in the minor U12 splicing processes, microarray analysis revealed that mutations in PRPF8 not only did not result in significant differences in splicing efficiency of rhodopsin, but no apparent changes in expression of U12-type intron genes and splicing processes was observed. Microarray analysis revealed a panel of differentially expressed genes mapped to the RP loci, and future work will determine their role in RP.

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“…Three of them were novel mutations (Val20Gly, Ser176Phe, Arg314fs16), and the other two mutations (Pro215Leu, Thr289Pro) have only been reported once in a brief mutation report without clinical details. 23 Clinical studies Figure 1 (A to E) shows the pedigree of the patients/families investigated. …”

Section: Mutation Analysismentioning

confidence: 99%

Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa

Schuster¹

2005

British Journal of Ophthalmology

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Three novel mutations (P215L, T289P, and 3811-2 A?G) in the rhodopsin gene in autosomal dominant retinitis pigmentosa in Spanish families

Cited by 12 publications

References 3 publications

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

Transcriptional expression ofcis-acting andtrans-acting splicing mutations cause autosomal dominant retinitis pigmentosa

Novel rhodopsin mutations and genotype-phenotype correlation in patients with autosomal dominant retinitis pigmentosa

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