Genetic Factors Modifying Clinical Expression of Autosomal Dominant RP

Daiger, Stephen P.; Shankar, Suma P.; Schindler, Alice B.; Sullivan, Lori S.; Bowne, Sara J.; King, Terri M.; Daw, E. Warick; Stone, Edwin M; Heckenlively, John R.

doi:10.1007/0-387-32442-9_1

Cited by 12 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nearly all human RP1 patients are heterozygous carriers (Jacobson et al, 2000; Daiger et al, 2005). It remains unclear why 15% reduction of ERG amplitudes in Rp1 +/− mice (Gao et al, 2002; Liu et al, 2003b; [Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous carriers of RP1 mutations exhibit late onset of retinopathies, whereas homozygous carriers tend to have earlier onset and more severe symptoms (Haider et al, 2002; Daiger et al, 2005). RP1 locus mutations account for 5–10% of all adRPs; the RP1 mutant allele derived from the UCLA-RP01 pedigree is the third most frequent mutation causing adRP (Blanton et al, 1991; Bowne et al, 1999; Pierce et al, 1999; Sullivan et al, 1999; Jacobson et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…The onset and severity of RP1 disease symptoms can vary greatly, even within the same pedigree with the same mutation. Such variations suggest the influence of genetic modifiers or environmental factors (Daiger et al, 2005). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa

Yamashita¹,

Liu²,

Gao³

et al. 2009

J. Neurosci.

View full text Add to dashboard Cite

Retinitis pigmentosa 1 (RP1) is a common inherited retinopathy with variable onset and severity. The RP1 gene encodes a photoreceptor-specific, microtubule-associated ciliary protein containing the doublecortin (DCX) domain. Here we show that another photoreceptor-specific Rp1-like protein (Rp1L1) in mice is also localized to the axoneme of outer segments (OSs) and connecting cilia in rod photoreceptors, overlapping with Rp1. Rp1L1؊/؊ mice display scattered OS disorganization, reduced electroretinogram amplitudes, and progressive photoreceptor degeneration, less severe and slower than in Rp1؊/؊ mice. In single rods of Rp1L1؊/؊, photosensitivity is reduced, similar to that of Rp1؊/؊. While individual heterozygotes are normal, double heterozygotes of Rp1 and Rp1L1 exhibit abnormal OS morphology and reduced single rod photosensitivity and dark currents. The electroretinogram amplitudes of double heterozygotes are more reduced than those of individual heterozygotes combined. In support, Rp1L1 interacts with Rp1 in transfected cells and in retina pull-down experiments. Interestingly, phototransduction kinetics are normal in single rods and whole retinas of individual or double Rp1 and Rp1L1 mutant mice. Together, Rp1 and Rp1L1 play essential and synergistic roles in affecting photosensitivity and OS morphogenesis of rod photoreceptors. Our findings suggest that mutations in RP1L1 could underlie retinopathy or modify RP1 disease expression in humans.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa

Yamashita¹,

Liu²,

Gao³

et al. 2009

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…As such, RP1 belongs to the second most frequent group of genes causing adRP (with PRPF31), following RHO which has the highest mutation rate [43,44]. Among the 37 dominant mutations, only 6 are missense.…”

Section: Discussionmentioning

confidence: 99%

Patients with Retinitis Pigmentosa due to RP1 Mutations Show Greater Severity in Recessive than in Dominant Cases

2012

J Clin Exp Ophthalmol

View full text Add to dashboard Cite

Study background: RP1 is a major gene for autosomal dominant retinitis pigmentosa and was reported in a few recessive families. Taken together, patients with RP1 mutations of both types of inheritance show a large spectrum in the severity of the disease. To get better insight in these clinical variations, patients with dominant and recessive retinitis pigmentosa due to RP1 mutations were investigated and their clinical features were compared.Methods: RP1 exons 2 and 3 were sequenced in 324 unrelated patients with presumed recessive retinitis pigmentosa (213 simplex, 68 multiplex) or cone rod dystrophy (27 simplex, 16 multiplex) and RP1 exon 4 hot spot (nt 1500-3216) was sequenced in 174 probands with dominant retinitis pigmentosa. Visual acuity and visual field were correlated with age using Pearson's linear coefficient and compared with a non parametric Wilcoxon test.Results: Two novel recessive null mutations (p.His31GlnfsX47, p.Val157TrpfsX16) were found in exon 2. Five novel dominant mutations (p.Lys673ArgfsX9, p.Tyr685X, p.Ile725TyrfsX13, p.Asn748IlefsX15, p.Ser862X) and the recurrent p.Gln679X and p.Ser911X mutations were found in exon 4. In recessive cases, decrease in visual acuity was at 21.8±5.8 years with visual acuity of 0.32±0.28. In dominant cases, decrease in visual acuity occurred later at 45.2±10.4 years in one group (0.54±0.28) and at 61.0±5.2 years in a second group (0.71±0.14). Visual field decrease was noticed earlier in recessive than in dominant cases (20.9±7.2 vs 49.0±16.3) but decrease level was similar (41.8±33.3% vs 34.5±31.7%). The rate of decrease was similar for visual acuity while for visual field it was higher in recessive than in dominant cases (3.93% per year vs 1.65% per year). Conclusions:The recessive patients had much more severe disease than dominant patients, with higher decrease rate in visual field and earlier onset in visual acuity decrease.

show abstract

“…The phenotype of RP is heterogeneous in that individuals in the same family and/or even the same sibship may have different symptoms despite carrying an identical genetic mutation. Phenotypic heterogeneity in RP may be attributed to modifying factors and/or environmental factors that have yet to be identified (Daiger, Shankar et al 2006). Mutations causing autosomal dominant (adRP), autosomal recessive (arRP) or X-linked RP (xlRP) have been identified in a total of 31 genes, with another 9 loci implicated by linkage (http://www.sph.uth.tmc.edu/RetNet) Within these disease-associated genes there may be one or many disease-causing alleles.…”

Section: 2 Retinitis Pigmentosamentioning

confidence: 99%

Investigating the Mechanism of Disease in the RP10 Form of Retinitis Pigmentosa

Spellicy

Cobb

et al. 2009

Retinal Degenerative Diseases

Self Cite

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is a disease characterized by its vast heterogeneity. Many genes are associated with RP, and the disease causing mutations identified in these genes are even more numerous. To date there are 15 genes that cause autosomal dominant RP (adRP) alone. The role of some of these genes, while complex and not completely understood, is somewhat intuitive in that they are involved in pathways such as phototransduction. However, the role of other genes in retinal disease is not as predictable due to their ubiquitous function and/or expression. One such gene is inosine monophosphate dehydrogenase 1 (IMPDH1) IMPDH1 is a gene involved in de novo purine synthesis and is ubiquitously expressed. IMPDH1 mutations account for 2% of all adRP cases and are a rare cause of Leiber Congenital Amaurosis. Despite its ubiquitous expression missense mutations in this gene cause only retinal degeneration. This paradox of tissue specific disease in the presence of ubiquitous expression has only recently begun to be explained. We have shown in a recent study that novel retinal isoforms of IMPDH1 exist and may account for the tissue specificity of disease. We have gone on to characterize these retinal isoforms both in our laboratory and in collaboration with Dr. Lizbeth Hedstrom’s laboratory at Brandeis University (Waltham, MA) in order to understand more about them. We believe that through clarifying the mechanism of disease in RP10 we will be equipped to consider treatment options for this disease.

show abstract

Genetic Factors Modifying Clinical Expression of Autosomal Dominant RP

Cited by 12 publications

References 21 publications

Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa

Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa

Patients with Retinitis Pigmentosa due to RP1 Mutations Show Greater Severity in Recessive than in Dominant Cases

Investigating the Mechanism of Disease in the RP10 Form of Retinitis Pigmentosa

Contact Info

Product

Resources

About