Linkage mapping of autosomal dominant retinitis pigmentosa (RP1) to the pericentric region of human chromosome 8

Blanton, Susan H.; Heckenlively, John R.; Cottingham, A. W.; Friedman, Jackie; Sadler, Lori A.; Wagner, Michael J.; Friedman, Lorraine H.; Daiger, Stephen P.

doi:10.1016/0888-7543(91)90008-3

Cited by 160 publications

(40 citation statements)

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“…However, within the same family, there is extensive variation in the age at which clinical disease is detected (7,9). Moreover, in some families such as the UCLA-RP01, two members who are homozygous for an RP1 mutation have substantially more severe retinal degeneration than other family members who are heterozygous for the mutation (9). The human RP1 gene encodes a protein of 2,156 aa, the function of which is currently unknown.…”

mentioning

confidence: 99%

Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 ( Rp1 ) gene

Gao

Cheon

Nusinowitz

et al. 2002

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

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110

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Retinitis pigmentosa (RP), a common group of human retinopathic diseases, is characterized by late-onset night blindness, loss of peripheral vision, and diminished or absent electroretinogram (ERG) responses. Mutations in the photoreceptor-specific gene RP1 account for 5-10% of cases of autosomal dominant RP. We generated a mouse model of the RP1 form of RP by targeted disruption of the mouse ortholog (Rp1) of human RP1. In Rp1 ؊͞؊ mice, the number of rod photoreceptors decreased progressively over a period of 1 year, whereas that of cone photoreceptors did not change for at least 10 months. Light and electron microscopic analysis revealed that outer segments of Rp1 ؊͞؊ rods and cones were morphologically abnormal and became progressively shorter in length. Before photoreceptor cell death, rhodopsin was mislocalized in inner segments and cell bodies of Rp1 ؊͞؊ rods. Rod ERG amplitudes of Rp1 ؊͞؊ mice were significantly smaller than those of Rp1 ؉͞؉ mice over a period of 12 months, whereas those of Rp1 ؉͞؊ mice were intermediate. The decreases in cone ERG amplitudes were slower and less severe than those in rods. These findings demonstrate that Rp1 is required for normal morphogenesis of photoreceptor outer segments and also may play a role in rhodopsin transport to the outer segments. The phenotype of Rp1 mutant mice resembles the human RP1 disease. Thus, these mice provide a useful model for studies of RP1 function, disease pathology, and therapeutic interventions. R etinitis pigmentosa (RP) is a common inherited retinopathy that affects Ϸ1 in 3,500 persons worldwide (1). Clinical findings in RP include progressive loss of night and peripheral vision that usually culminates in severe visual impairment or blindness. The disease is characterized by an abnormal or absent response on electroretinography (ERG) and is associated with retinal atrophy, deposition of pigment, and attenuation of retinal vessels. RP is heterogeneous clinically and genetically (2).We identified a gene, designated RP1, that is mutated in families with the RP1 form of autosomal dominant RP (3-8).The patients who are heterozygous for the RP1 mutations have very similar classic type 2 autosomal dominant RP phenotypes with relatively late onset of night blindness (usually by the third decade of life). However, within the same family, there is extensive variation in the age at which clinical disease is detected (7, 9). Moreover, in some families such as the UCLA-RP01, two members who are homozygous for an RP1 mutation have substantially more severe retinal degeneration than other family members who are heterozygous for the mutation (9). The human RP1 gene encodes a protein of 2,156 aa, the function of which is currently unknown. However, its N terminus shares significant homology with that of human doublecortin (DCX), a mutant form of which is involved in cerebral cortical abnormalities (10,11). This region of DCX is known to interact with microtubules (12, 13).To understand the function of the RP1 protein in the retina and the mechanism of reti...

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confidence: 99%

Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 ( Rp1 ) gene

Gao

Cheon

Nusinowitz

et al. 2002

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

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110

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“…This pedigree has 2 loops and 2 multiply married individuals. As shown in Blanton et al [37], this pedigree had to be split into 3 pieces because computation on the whole family together was prohibitively long. Here we leave the loops in.…”

Section: Resultsmentioning

confidence: 99%

Automatic Selection ofLoop Breakers for GeneticLinkage Analysis

1998

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Pedigree loops pose a difficult computational challenge in genetic linkage analysis. The most popular linkage analysis package, LINKAGE, uses an algorithm that converts a looped pedigree into a loopless pedigree, which is traversed many times. The conversion is controlled by user selection of individuals to act as loop breakers. The selection of loop breakers has significant impact on the running time of the subsequent linkage analysis. We have automated the process of selecting loop breakers, implemented a hybrid algorithm for it in the FASTLINK version of LINKAGE, and tested it on many real pedigrees with excellent performance. We point out that there is no need to break each loop by a distinct individual because, with minor modification to the algorithms in LINKAGE/FASTLINK, a single individual that participates in multiple marriages can serve as a loop breaker for several loops. Our algorithm for finding loop breakers, called LOOPBREAKER, is a combination of: (1) a new algorithm that is guaranteed to be optimal in the special case of pedigrees with no multiple marriages and (2) an adaptation of a known algorithm for breaking loops in general graphs. The contribution of this work is the adaptation of abstract methods from computer science to a challenging problem in genetics.

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“…This was named the "RP1" locus based on preliminary linkage mapping to chromosome 1 (later shown to be incorrect). Subsequent linkage testing assigned the disease locus in this family to human chromosome 8q11-q12 (Blanton et al, 1991). Linkage testing in an Australian adRP family led to identification of a second RP1 family.…”

Section: The Rp1 Locusmentioning

confidence: 99%