Homozygous tandem duplication within the gene encoding the β-subunit of rod phosphodiesterase as a cause for autosomal recessive retinitis pigmentosa

Bayés, Mònica; Giordano, Mara; Balcells, Susana; Grinberg, Daniel; Vilageliu, L; Martínez, Israel Borrajero; Ayuso, Carmen; Benı́tez, Javier; Ramos-Arroyo, María A.; Chivelet, Pilar; Solans, Teresa Torrent; Valverde, Diana; Amselem, Serge; Goossens, Michel; Baiget, Montserrat; Gonzàlez‐Duarte, Roser; Besmond, Claude

doi:10.1002/humu.1380050307

Cited by 60 publications

(24 citation statements)

References 26 publications

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“…This latter gene encodes the b-subunit of retinal rod cGMP phosphodiesterase, a key enzyme involved in phototransduction in rod photoreceptor cells. 4 ARRP could also be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) (MIM276900), which represents the most common form of hereditary deafblindness in humans. It has a prevalence of B1/20 000 and represents 50% of the cases with deafblindness.…”

Section: Introductionmentioning

confidence: 99%

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family

Hmani-Aifa¹,

Benzina

Zulfiqar

et al. 2008

Eur J Hum Genet

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Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23 -24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.

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Section: Introductionmentioning

confidence: 99%

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family

Hmani-Aifa¹,

Benzina

Zulfiqar

et al. 2008

Eur J Hum Genet

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“…However, mutations in the beta subunit of the rod cGMP-phosphodiesterase gene, [8][9][10][11] in the ATP binding cassette receptor gene, 12 in the TULP1 gene, 13 in the alpha subunit of the rod cGMP gated channel, 14 and in the USH2A gene 15 have been detected in a small percentage of Spanish ARRP families. These data indicate that other genes play a part in the degeneration process of the retina in the remaining families.…”

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confidence: 99%

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

Bernal

Calaf²,

Garcia‐Hoyos³

et al. 2003

Journal of Medical Genetics

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R etinitis pigmentosa (RP), which occurs in about 1 in 3000-7000 people in Spain, is inherited in an autosomal dominant manner in 12% of cases, in an autosomal recessive way in 39%, and in an X linked manner in 4% of cases.1 This leaves 41% of RP cases with a simplex form and 4% in which the transmission pattern is unclear.The different genes that have been implicated in retinal degeneration are known or assumed to be expressed in the photoreceptor cells of the retina or in the retinal pigment epithelium (RPE). The large number of RP genes identified can be grouped into a number of functional classes: (1) proteins of the visual cascade, (2) proteins of the visual cycle, (3) photoreceptor cell transcription factors, (4) proteins related to catabolic processes, and (5) 14 and in the USH2A gene 15 have been detected in a small percentage of Spanish ARRP families. These data indicate that other genes play a part in the degeneration process of the retina in the remaining families.We analysed the involvement of three additional genes, the RPE retinal G protein coupled receptor (RGR), the cellular retinol binding protein (CRBP1), and the crumbs homologue 1 (CRB1) (table 1) in 92 ARRP Spanish families.RGR is an integral membrane protein that is expressed in the cytoplasm of RPE and Müller cells. 16 It is a member of a large family of G protein coupled receptors and shows considerable overall homology to the visual pigments and retinochromes. Under light conditions, RGR converts all-transretinal to 11-cis-retinal, whereas the reverse isomerisation occurs within rhodopsin.CRBP1 belongs to a family of cytosolic proteins whose members bind various hydrophobic ligands. This protein is a component in the retinal pigment epithelium where it is believed to function in intracellular storage and transport of retinol.The CRB1 gene is expressed in human retina and brain. It exhibits alternative splicing at its 3′ end and the four classes of mRNA are predicted to encode four different proteins, two of which are found in human retina. 17 Given its homology to the Drosophila Crumbs protein that is required for polarity and adhesion in embryonic epithelia, it has been postulated that the role of CRB1 in vertebrate photoreceptors may be in cell adhesion and photoreceptor morphogenesis. A role in localising the phototransduction complex to the apical membrane of the photoreceptors has been proposed owing to the specific expression of CRB1. MATERIALS AND METHODS FamiliesThis study comprises 92 ARRP families including four families with retinitis punctata albescens (50 consanguineous and 42 non-consanguineous pedigrees). Most of the families were examined ophthalmologically at the Hospital de la Santa Creu i Sant Pau in Barcelona or at the Fundación Jiménez Díaz in Madrid. The clinical diagnosis of RP was based on ophthalmological examination including measurements of visual acuity, ophthalmoscopy, dark adaptation, ocular tension by air tonometer, perimetry, and electroretinogram amplitudes according to ISCEV protocols. 18 METHODSBlood sam...

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“…2) mouse genes led to the identification of mutations in the ␤-subunit of cGMP-phosphodiesterase (3)(4)(5) and tubby-like protein 1 (TULP1, refs. 6 and 7) in individuals affected with autosomal recessive RP.…”

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A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse

Akhmedov

Piriev

Chang

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

190

159

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The rd7 mouse, an animal model for hereditary retinal degeneration, has some characteristics similar to human flecked retinal disorders. Here we report the identification of a deletion in a photoreceptor-specific nuclear receptor (mPNR) mRNA that is responsible for hereditary retinal dysplasia and degeneration in the rd7 mouse. mPNR was isolated from a pool of photoreceptorspecific cDNAs originally created by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas. Localization of the gene corresponding to mPNR to mouse Chr 9 near the rd7 locus made it a candidate for the site of the rd7 mutation. Northern analysis of total RNA isolated from rd7 mouse retinas revealed no detectable signal after hybridization with the mPNR cDNA probe. However, with reverse transcription-PCR, we were able to amplify different fragments of mPNR from rd7 retinal RNA and to sequence them directly. We found a 380-nt deletion in the coding region of the rd7 mPNR message that creates a frame shift and produces a premature stop codon. This deletion accounts for more than 32% of the normal protein and eliminates a portion of the DNA-binding domain. In addition, it may result in the rapid degradation of the rd7 mPNR message by the nonsense-mediated decay pathway, preventing the synthesis of the corresponding protein. Our findings demonstrate that mPNR expression is critical for the normal development and function of the photoreceptor cells.

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Homozygous tandem duplication within the gene encoding the β-subunit of rod phosphodiesterase as a cause for autosomal recessive retinitis pigmentosa

Cited by 60 publications

References 26 publications

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse

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