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At least 55 records · Page 3Linked to original sources
PubMed2004

Arg120stop nonsense mutation in the RP2 gene: mutational hotspot and germ line mosaicism?

Mutations in the RP2 gene account for up to 20% of X-linked recessive retinitis pigmentosa (RP). Arg120stop is to date the most frequently reported mutation found in RP2. Mutation screening was performed during the course of a large screening program of retinal degenerative disorders (RDDs) in South Africa using exon 1 and 2 of RP2 in 20 unrelated families with an X-linked mode of retinal degenerative inheritance. Direct sequencing analysis revealed a C-->T transition at position 358 in the proband in a family of German origin. Subsequent analysis revealed that this Arg120stop mutation cosegregated with the disease in an additional affected family member. The nonsense mutation, Arg120stop, could not however, be detected in the somatic cells of the obligate carrier female. This, the first report of a germ line mutation for a family with RP, has many implications for genetic counseling of retinal degeneration (RD). To avoid inaccurate risk assessment for RP due to epigenetic events, such as the rare occurrence of germ line mosaicism, genetic counseling in families with XLRP should always be guided by molecular testing.

Adult↗
PubMed1991

Genetic localisation of the RP2 type of X linked retinitis pigmentosa in a large kindred.

Genetic linkage and deletion studies have led to the proposal that there are at least two loci on the X chromosome which are responsible for X linked retinitis pigmentosa (XLRP). One locus (RP3) has been closely defined by genetic linkage and deletion analyses and localised to the region between the ornithine transcarbamylase (OTC) and chronic granulomatous disease (CYBB) loci in Xp21.1-p11.4. The other locus (RP2) has been assigned by linkage analysis alone to region Xp11.4-p11.2, but its localisation is less well defined. The results of a multipoint linkage analysis of a single large XLRP kindred using eight informative loci provide further evidence on the localisation of RP2 to this region. The maximum likelihood location of this locus shows a multipoint lod score of 7.17 close to DXS255 (in Xp11.22) and TIMP (in Xp11.3-p11.23), neither of which show recombination with RP2, in an area extending from 2 cM proximal to DXS7 to 1 cM distal to DXS14 (approximate 95% confidence limits).

Bayes Theorem↗
PubMed2000

Cloning, Sequencing and Preliminary Expression of Human RP2 Gene.

RP2 is an X-linked retinitis pigmentosa gene, which was newly discovered by positional cloning. A polymerase chain reaction (PCR) was conducted to screen a full-length cDNA fragment, defined as hRP2a, which included the coding region of hRP2, in a human retina cDNA library. HRP2a gene was cloned into the pJLA503 vector and hRP2 gene was subcloned into the expression vector pP(RO)EX HTa. Polymorphism was demonstrated at two sites through DNA sequencing. The recombinant pP(RO)RP2 was transformed into Escherichia coli strain DH5alpha and the expression of a 6xHis tagged hRP2 fusion protein was induced by IPTG. Band density scanning of stained gel was performed to estimate the percentage of the recombinant protein in the total bacterial protein. The ratio was 7% when the expression was induced at 30 degrees and was 5.6 % at 37 degrees. The cloning and expression of hRP2 gene in E.coli established a basis for the further purification and studies of RP2 for its physiochemical identity, immunohistochemistry and structure-function relationship.

Journal Article↗
PubMed1997

Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci RP2 and RP3 on proximal Xp.

PURPOSE: Proximal Xp harbors many inherited retinal disorders, including retinitis pigmentosa (RP) and congenital stationary night blindness, both of which display genetic heterogeneity. X-linked congenital stationary night blindness (CSNBX) is a nonprogressive disease causing night blindness and reduced visual acuity. Distinct genetic loci have been reported for CSNBX at Xp21.1, which is potentially allelic with the RP3 gene, and at Xp11.23, which is potentially allelic with the RP2 gene. The study to identify the RP2 gene led to an extended study of families with potentially allelic diseases that include CSNBX. METHODS: Haplotype analysis of a family diagnosed with CSNBX was performed with 17 polymorphic markers on proximal Xp covering previously identified loci for CSNBX and XLRP. Two-point and multipoint lod scores were calculated. RESULTS: Informative recombinations in this family define a locus for CSNBX (CSNB4) with flanking markers DXS556 and DXS8080 on Xp11.4 to Xp11.3, an interval spanning approximately 5 to 6 cM. A maximum lod score of 3.2 was calculated for the locus order DXS556-1 cM-(CSNB4-DXS993)-2 cM-DXS1201. CONCLUSIONS: The results describe a new localization for CSNBX (CSNB4) between the RP2 and RP3 loci on proximal Xp. CSNB4 is not allelic with any previously reported XLRP loci; however, the interval overlaps the locus reported to contain the cone dystrophy (COD1) gene, and both diseases are nonrecombinant with DXS993. Because mutations in the RPGR gene to date account for disease in only a small proportion of RP3 families, the possibility that this new locus (CSNB4) also segregates with an as yet unidentified XLRP locus cannot be excluded.

Chromosome Mapping↗
PubMed2000

Novel mutation in RP2 gene in two brothers with X-linked retinitis pigmentosa and mtDNA mutation of leber hereditary optic neuropathy who showed marked differences in clinical severity.

PURPOSE: To report the identification of a novel mutation of the RP2 gene in two Japanese brothers with X-linked retinitis pigmentosa of a differing clinical severity. The mother was a carrier of both retinitis pigmentosa and optic atrophy. METHODS: The older brother had a severe form of retinitis pigmentosa associated with macular degeneration and total optic atrophy, whereas the younger brother presented typical X-linked retinitis pigmentosa. RESULTS: Each patient exhibited a novel 2-bp insertion at codon 278 in exon 3 of the RP2 gene as well as a 11778 mutation in mitochondrial DNA. This suggests that the older brother may have developed Leber hereditary optic neuropathy as well as retinitis pigmentosa. CONCLUSION: Molecular testing confirmed the clinical diagnosis in each case. However, such testing did not explain the differences in the severity of the ophthalmoscopic findings between the two brothers.

Adolescent↗
PubMed1999

Homozygous deletion of the CYP21A-TNXA-RP2-C4B gene region conferring C4B deficiency associated with recurrent respiratory infections.

The central class III region of the human major histocompatibility complex contains highly polymorphic genes that are associated with immune disorders and may serve as susceptibility factors for viral infections. Many HLA haplotype specific rearrangements, duplications, conversions and deletions, occur frequently in the C4 gene region. Genetic deficiencies of complement components are associated with recurrent occurrence of bacterial infections. We have studied the complement profile and the class III genes 5'-RP1-C4A-CYP21A-TNXA-RP2-C4B-CYP21B-TNXB -3' in a 4-year-old Caucasian patient. He has suffered from several pneumonias caused by respiratory viruses, eight acute otitis media, prolonged respiratory infections and urinary tract infection. Complement C4 was constantly low, but the other complement components, from C1 to C9, C1INH, factor B and properdin, were within normal limits. Immunological evaluation gave normal lymphocyte numbers and functions with the exception of subnormal T cell response to pokeweed mitogen. Molecular studies of the C4 gene region in the patient revealed homozygous deletion of CYP21A-TNXA-RP2-C4B generating total deficiency of C4B and the flanking 5' region up to C4A, and in the father a missing CYP21A gene. Further investigations are needed to elucidate the relationship between C4B deficiency and susceptibility to infections.

Adult↗
PubMed1968

An investigation of acid-soluble nuclear proteins of human leucocytes in relation to fraction RP2-L, a component of neoplastic cells.

1. The claim that tumour cells contain a specific nuclear protein was investigated. The presence of this component was confirmed in Walker tumour cells by the chromatography on CM-cellulose of nuclear proteins labelled with [(14)C]lysine. This protein was studied further in a number of human leucocyte cells. 2. The labelling of leucocyte nuclear proteins with [(14)C]lysine was attempted during incubation and culture in vitro. Incorporation of the label into acid-soluble nuclear proteins was highest in normal lymphocytes cultured with phytohaemagglutinin, followed by chronic-myeloid-leukaemic leucocytes and mixed samples of normal leucocytes incubated in plasma. Little incorporation was seen in similar extracts of chronic-lymphatic or normal leucocytes. 3. Lymphocytes were the only cells that gave nuclear extracts with amino acid analysis similar to that of unfractionated histones. 4. Little of the [(14)C]lysine in nuclear extracts of incubated leucocytes proved to be of chromosomal origin. No evidence was found of an RP2-L component in the highly labelled nuclear extracts of phytohaemagglutinin-treated lymphocytes until after 6 days of culture with [(14)C]lysine. This component was soluble in saline. 5. Evidence is presented that fraction RP2-L is a non-histone protein constituent of cell nuclei whose labelling with [(14)C]lysine may be dependent on the metabolic state of the cell. Thus this component is not specific to the neoplastic state.

Journal Article↗
PubMed1992

X-linked retinitis pigmentosa: functional phenotype of an RP2 genotype.

Rod- and cone-mediated function was studied with psychophysics and electroretinography in members of an X-linked retinitis pigmentosa pedigree with the RP2 genotype. An asymptomatic hemizygote with an early stage of the disease had cone dysfunction in the mid-periphery and an abnormal cone electroretinogram (ERG); rod function was normal. Hemizygotes with more advanced disease had cone and rod dysfunction in the mid-peripheral retina and cone dysfunction in the far periphery; cone and rod ERGs were abnormal. At very advanced stages, there was an absolute mid-peripheral scotoma and marked cone and rod dysfunction in the far peripheral and central retina. Cone and rod ERGs were severely abnormal or not detectable. Heterozygotes showed tapetal-like reflexes, patches of pigmentary retinopathy, and a range of functional findings from no detectable abnormalities to moderate levels of retinal dysfunction. There were regions of normal function adjacent to dysfunctional patches that had greater cone than rod sensitivity losses or comparable cone and rod losses. The results suggest that the phenotype of this RP2 genotype of X-linked retinitis pigmentosa, unlike other forms of retinitis pigmentosa, is first expressed as a cone photoreceptor system dysfunction, and as the disease progresses, both rod and cone systems are involved.

Adult↗
PubMed2026

InsightRP2-An Interdisciplinary Approach Toward Therapy Development in RP2-Associated Retinopathy.

Advancing the development of specific gene therapies for rare genetic eye disorders is a major challenge in modern translational vision research. It requires integrated clinical, molecular, mechanistic, and regulatory expertise, yet these aspects are often addressed in isolation. Combining complementary skills, knowledge, and expertise within an integrated, highly interactive research framework has the capacity to drive and advance therapeutic development. Moreover, early-stage involvement of patients and targeted clinical observation, alongside molecular and therapeutic research, potentially enable clinical trial readiness and support the translation of preclinical therapeutic innovations into clinical care. In this Perspective article, we present the InsightRP2 framework, an integrated translational strategy that incorporates clinical data, artificial intelligence-supported imaging analysis, experimental disease modeling, and adeno-associated virus design with the aim to facilitate the development of a targeted gene therapy for RP2-associated retinitis pigmentosa.

AAV↗
PubMed2001

Phenotype associated with an R120X nonsense mutation in the RP2 gene in a Japanese family with X-linked retinitis pigmentosa.

We examined a Japanese family with X-linked retinitis pigmentosa (RP) associated with a nonsense mutation, R120X, in the RP2 gene. The 26-year-old proband presented at the age of seven years with a two-year history of night blindness. Visual disability worsened with increasing age. At age 24, visual acuity was 0.08 in both eyes. Testing for refractive error indicated mild myopia. Visual fields showed bilateral-constriction to 10 degrees. He had central macular areolar sclerosis in both eyes. Two maternal uncles had vision of light perception to hand movement in their early forties together with dense bilateral cataracts. The ocular phenotype of this family with R120X was considered severe; reported phenotypes associated with this mutation have not been uniform.

Amino Acid Sequence↗
PubMed1994

Retinitis pigmentosa families showing apparent X linked inheritance but unlinked to the RP2 or RP3 loci.

Three families with retinitis pigmentosa (RP) are described in which the disorder shows apparent X linked inheritance but does not show linkage to the RP2 and RP3 regions of the short arm of the X chromosome. The families are also inconsistent with a localisation of the disease gene between DXS164 and DXS28. In one case, reassessment of the family in the light of these results suggested that the family may have an autosomal dominant form of RP. The remaining two families are consistent with X linkage and suggest the possibility of a new X linked RP (XLRP) locus. These families highlight the difficulties in determining the mode of inheritance on the basis of pedigree structure and clinical data alone. Molecular genetics plays an important role in confirming the mode of inheritance and in detecting potential misclassifications, particularly in a group of disorders as heterogeneous as RP. They emphasise that caution is required in genetic counselling of RP families, particularly in the absence of any molecular genetic analysis.

Adult↗
PubMed1998

Linkage analysis of X-linked cone-rod dystrophy: localization to Xp11.4 and definition of a locus distinct from RP2 and RP3.

Progressive X-linked cone-rod dystrophy (COD1) is a retinal disease affecting primarily the cone photoreceptors. The COD1 locus originally was localized, by the study of three independent families, to a region between Xp11.3 and Xp21.1, encompassing the retinitis pigmentosa (RP) 3 locus. We have refined the COD1 locus to a limited region of Xp11.4, using two families reported elsewhere and a new extended family. Genotype analysis was performed by use of eight microsatellite markers (tel-M6CA, DXS1068, DXS1058, DXS993, DXS228, DXS1201, DXS1003, and DXS1055-cent), spanning a distance of 20 cM. Nine-point linkage analysis, by use of the VITESSE program for X-linked disorders, established a maximum LOD score (17.5) between markers DXS1058 and DXS993, spanning 4.0 cM. Two additional markers, DXS977 and DXS556, which map between DXS1058 and DXS993, were used to further narrow the critical region. The RP3 gene, RPGR, was excluded on the basis of two obligate recombinants, observed in two independent families. In a third family, linkage analysis did not exclude the RPGR locus. The entire coding region of the RPGR gene from two affected males from family 2 was sequenced and was found to be normal. Haplotype analysis of two family branches, containing three obligate recombinants, two affected and one unaffected, defined the COD1 locus as distal to DXS993 and proximal to DXS556, a distance of approximately 1.0 Mb. This study excludes COD1 as an allelic variant of RP3 and establishes a novel locus that is sufficiently defined for positional cloning.

Alleles↗