Autosomal dominant retinitis pigmentosa: A novel mutation at the peripherin/RDS locus in the original 6p-linked pedigree

Farrar, G. Jane; Kenna, Paul F.; Jordan, Siobhán A.; Kumar‐Singh, Rajendra; Humphries, Marian M.; Sharp, Elizabeth M.; Sheils, Denise M.; Humphries, Peter

doi:10.1016/s0888-7543(05)80193-4

Cited by 45 publications

(18 citation statements)

References 13 publications

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“…At least 30 genes have been implicated in the genetics of retinitis pigmentosa, many of which encode photoreceptor-specific proteins such as the structural protein peripherin (2), rod outer segment membrane protein-1 (3), rod cGMP phosphodiesterase (4), and rhodopsin (5). Extensive studies of retinal degeneration in animal models such as the rd (6) and the rds (7) mice, as well as several other knock-out and transgenic mice, suggest that apoptosis is the common feature of photoreceptor cell death in all the models (8).…”

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confidence: 99%

“…1): an increase in intracellular Ca 2ϩ activates calpain, a Ca 2ϩ -dependent cysteine protease (17), which can cleave the proapoptotic Bcl-2 family protein bid. Interaction of truncated bid (t-bid) with the mitochondrial permeability transition pore (PTP) 2 causes mitochondrial membrane potential loss (⌬⌿ m ), leading to the release of cytochrome c. The increase in cytoplasmic cytochrome c causes the assembly of the apoptosome (18), leading to the activation of caspases, which cleave downstream death substrates and activate endonucleases that cleave genomic DNA into fragments resulting in the apoptotic nuclear morphology (19).…”

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Calcium-induced Calpain Mediates Apoptosis via Caspase-3 in a Mouse Photoreceptor Cell Line

Sharma¹,

Rohrer

2004

Journal of Biological Chemistry

138

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The rd mouse, an accepted animal model for photoreceptor degeneration in retinitis pigmentosa, has a recessive mutation for the gene encoding the ␤-subunit of the cGMP phosphodiesterase. This mutation results in high levels of cGMP, which leaves an increased number of the cGMP-gated channels in the open state, thus allowing intracellular calcium (Ca 2؉ ) to rise to toxic levels, and rapid photoreceptor degeneration follows. To delineate the events in rd photoreceptor degeneration, we demonstrated an increase in calpain and caspase-3 activity, hypothesizing that Ca 2؉ -mediated apoptosis in photoreceptors is mediated by calpain, involving mitochondrial depolarization and caspase-3 activation. To examine this hypothesis further, a murine photoreceptor-derived cell line (661W) was treated with the Ca 2؉ ionophore A23187, cGMP-gated channel agonist 8-bromocGMP, or phosphodiesterase inhibitor isobutylmethylxanthine to mimic the increased Ca 2؉ influx seen in the rd photoreceptors. Ca 2؉ -induced cell death in 661W cells was found to be mediated by calpain and caspase-3 and could be completely inhibited by the calpain inhibitor SJA6017, implicating both calpain and caspases in the apoptotic process. The apoptotic events correlated in an SJA6017-inhibitable manner with bid cleavage, mitochondrial depolarization, cytochrome c release, and caspase-3 and -9 activation. We concluded that Ca 2؉ influx in the rd model of photoreceptor degeneration leads to the activation of the cysteine protease calpain, which executes apoptosis via modulation of caspase-3 activity.

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confidence: 99%

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confidence: 99%

Calcium-induced Calpain Mediates Apoptosis via Caspase-3 in a Mouse Photoreceptor Cell Line

Sharma¹,

Rohrer

2004

Journal of Biological Chemistry

138

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“…Macte In2ehearn et al, 1992Berson, 1993Fishman et al, 1991Sung et al, 1991aSung et al, 1991bRao et al, 1994Macke et al, 1993Macke et al, 1993Reig et al, 1994Keen et al, 1991Sheffield et al, 1991Dryja et al, 1993Keen et al, 1991Sullivan et al, 1993Berson, 1993Berson, 1993Fishman et al, 1992aSung et al, 1991aSung et al, 1991bFarrar et al, 1991cSung et al, 1991aSheffield et al, 1991Fishman et al, 1992b Meins et al, 1993Kajiwara et al, 1992Weleber et al, 1993Nichols et al, 1993Wells et al, 1993Wroblewski et al, 1994Wells et al, 1993Kajiwara et al, 1991Farrar et al, 1992Saga et al, 1993Kajiwara et al, , 1991 Kajiwara et al, Wells et al, 1993 the preservation of peripheral vision and is found to be caused by the mutation at codon Arg-172-Gln, Arg-172-Trp, and Tyr-258-stop. A substitution mutation in a highly conserved glycine (Gly-167-Asp) seems to cause butterfly dystrophy which is characterized by the abnormal pigment material at the level of retinal pigment epithelium.…”

Section: Mutations In the Intradiscal Domainmentioning

confidence: 99%

Retinitis pigmentosa and related disorders: Phenotypes of rhodopsin and peripherin/RDS mutations

Shastry

1994

Am. J. Med. Genet.

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Retinitis pigmentosa comprises a group of clinically variable and genetically heterogeneous inherited disorders of the retina. It is estimated that approximately 1.5 million people throughout the world are affected by this disease. It is a slowly progressive disorder and causes loss of night vision and peripheral visual field in adolescence. It can be inherited through an autosomal dominant, recessive, or X-linked mode; the autosomal dominant form is considered to be the mildest form. Molecular genetic studies on the autosomal dominant disorder have shown that, in some families, genes encoding the rhodopsin and peripherin/RDS map very close to the disease loci identified previously by the systematic linkage analyses. These results, together with the observation that a recessive nonsense mutation in the Drosophila opsin gene causes photoreceptor degeneration, prompted an extensive search for the alterations in the human rhodopsin and peripherin/RDS genes in families with autosomal dominant retinitis pigmentosa. As a result, several distinct rhodopsin and peripherin/RDS mutations have been found in approximately 30% of all autosomal dominant cases. A wide variety of clinical expression of the disorder even within a family with the same mutation, its late onset, slow progression, and cone degeneration clearly suggest that some other factors or genes in addition to rhodopsin are responsible for the phenotypic expression of the disorder. In this article, an attempt is made to highlight some of these recent developments and to correlate the various mutations and the phenotypes.

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“…In 1991 two groups reported the identification of heterozygous mutations in patients with autosomal dominant retinitis pigmentosa: Cys118/119del(3bp) by Farrar et al [1991] and Pro219del(3bp), Pro216Leu and Leu185Pro by Kajiwara et al [1991]. Suprisingly, peripherin/RDS mutations were found not to be restricted to the retinitis pigmentosa phenotype, but could also be detected in various other forms of retinal dystrophies, in which there is a more general or even cone-specific degeneration [Wells et al, 1993].…”

Section: Peripherin/rds Gene Mutations In Human Retinal Dystrophiesmentioning

confidence: 99%

The Role of the Peripherin/<i>RDS</i> Gene in Retinal Dystrophies

Kohl¹,

Giddings²,

Besch

et al. 1998

Cells Tissues Organs

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Peripherin/RDS is a transmembrane glycoprotein expressed in vertebrate photoreceptors. It is located at the rim of the disc membranes of the photoreceptor outer segments, where it is thought to play an important role in folding and stacking of the discs. Initially, the identification of a mutation in the rds mouse model defined the role of this gene in hereditary retinal dystrophies. To date over 60 different mutations have been reported in human retinal diseases, with most being restricted to single families. A characteristic of mutations in the peripherin/RDS gene is the broad phenotypic spectrum in patients, and the variability in clinical expression, even within families. Thus, genotype-phenotype correlations are difficult and only reliable for a minority of mutations.

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Autosomal dominant retinitis pigmentosa: A novel mutation at the peripherin/RDS locus in the original 6p-linked pedigree

Cited by 45 publications

References 13 publications

Calcium-induced Calpain Mediates Apoptosis via Caspase-3 in a Mouse Photoreceptor Cell Line

Calcium-induced Calpain Mediates Apoptosis via Caspase-3 in a Mouse Photoreceptor Cell Line

Retinitis pigmentosa and related disorders: Phenotypes of rhodopsin and peripherin/RDS mutations

The Role of the Peripherin/<i>RDS</i> Gene in Retinal Dystrophies

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