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C F Inglehearn

Publications and source records attributed to C F Inglehearn.

At least 55 records · Page 3Linked to original sources
PubMed1995

A YAC contig spanning the dominant retinitis pigmentosa locus (RP9) on chromosome 7p.

The dominant retinitis pigmentosa locus RP9 has previously been localized to 7p13-p15, in the interval D7S526-D7S484. We now report refinement of the locus to the interval D7S795-D7S484 and a YAC contig of approximately 4.8 Mb spanning this region and extending both distally and proximally from it. The contig was constructed by STS content mapping and physically orders 29 STSs in 28 YAC clones. The order of polymorphic markers in the contig is consistent with a genetic map that has been assembled using haplotype data from the CEPH pedigrees. This contig will provide a primary resource for the construction of a transcriptional map of this region and for the identification of the defective gene causing this form of adRP.

Base Sequence↗
PubMed1995

Linkage of congenital hereditary endothelial dystrophy to chromosome 20.

Congenital heredity endothelial dystrophy (CHED) is a rare autosomal dominant disorder of the cornea. We have performed genetic linkage analysis with microsatellite markers on a seven generation British pedigree. Two-point linkage analysis revealed significant linkage of CHED (lod score >3) with seven marker loci mapping to chromosome 20. The highest observed lod score was 7.20 (theta=0.026) with marker D20S114. Multipoint analysis gave a maximum lod score of 9.34 between D20S48 and D20S471. This 2.7cM region lies within 30 cM region recently assigned to posterior polymorphous dystrophy (PPD). PPD and CHED may therefore be allelic, or alternatively it is possible that more than one gene in this region is responsible for these two corneal dystrophies.

Chromosome Mapping↗
PubMed1995

An eighth locus for autosomal dominant retinitis pigmentosa is linked to chromosome 17q.

Retinitis pigmentosa is one of the most common causes of severe visual handicap in middle to late life. Prior to this report, seven loci had previously been mapped for the autosomal dominant form of this disorder (adRP). We now report the identification of a novel adRP locus on chromosome 17q. To map the new locus, we performed linkage analysis with microsatellite markers in a large South African kindred. After exclusion of 13 RP candidate gene loci (including rhodopsin and peripherin-RDS), we obtained significant positive lod scores at zero recombination fraction (theta = 0) for D17S808 (Z = 4.63) and D17S807 (Z = 5.69). Multipoint analysis gave a maximum lod score of 8.28 between these two markers. From haplotype analysis, the disease locus lies in the interval between markers D17S809 and D17S942. Three candidate genes for retinal dystrophies map to this chromosomal region and these genes are currently being investigated for possible involvement with adRP in this family.

Adult↗
PubMed1995

Bimodal expressivity in dominant retinitis pigmentosa genetically linked to chromosome 19q.

A clinical, psychophysical, and electrophysiologic study was undertaken of two autosomal dominant retinitis pigmentosa pedigrees with a genetic mutation assigned to chromosome 19q by linkage analysis. Members with the abnormal haplotype were either symptomatic with adolescent onset nyctalopia, restricted visual fields, and non-detectable electroretinographic responses by 30 years of age, or asymptomatic with normal fundus appearance and minimal or no psychophysical or electroretinographic abnormalities. There was no correlation in the severity in parents and their offspring. Pedigree analysis suggested that although the offspring of parents with the genetic mutation were at 50% risk of having the genetic defect, the risk of being symptomatic during a working lifetime was only 31%. Such bimodal phenotypic expressivity in these particular pedigrees may be explained by a second, allelic genetic influence and may be a phenomenon unique to this genetic locus. Genetic counselling in families expressing this phenotype can only be based on haplotype analysis since clinical investigations, even in the most elderly, would not preclude the presence of the mutant gene.

Adult↗
PubMed1994

Identification of a sixth locus for autosomal dominant retinitis pigmentosa on chromosome 19.

We report the mapping of a sixth locus for autosomal dominant retinitis pigmentosa (adRP) to 19q13.4. After a total genome linkage search using over 300 markers in a single large pedigree, marker loci on the long arm of chromosome 19 showed significant linkage with the disease locus. Since the mapping information for the marker loci used in this study was derived from two different genome maps, we established genetic distances between relevant marker loci so that linkage information could be combined from both maps. A conventional three point analysis between the adRP phenotype and markers D19S180 and D19S214 gave a maximum lod score of 4.87. Combining data from these and other markers, we used the recently described multiple two point programme FASTMAP to simulate a multipoint analysis of the full data set. This gave a lod score of 5.34 in the interval between markers D19S180 and D19S214. Recently this laboratory has also reported the linkage of another form of retinal degeneration known as cone-rod dystrophy (CRD) to a genetically different set of markers from 19q. Linkage data presented here clearly supports the existence of two separate retinal genes in this part of the genome.

Chromosome Mapping↗
PubMed1994

Ocular findings associated with a 3 base pair deletion in the peripherin-RDS gene in autosomal dominant retinitis pigmentosa.

Affected members of a family with autosomal dominant retinitis pigmentosa were found to have a 3 base pair deletion at codon 118 or 119 of the retinal degeneration slow gene. This mutation causes the loss of a highly conserved cysteine residue in the predicted third transmembrane domain of peripherin-rds, a photo-receptor specific structural glycoprotein localised to both rod and cone outer segment disc membranes. Four of these individuals underwent detailed clinical, psychophysical, and electroretinographic testing in order to characterise their photoreceptor dysfunction. Nyctalopia was reported early in the second decade by all patients. Global rod and cone dysfunction was recorded by the third decade with severe reduction of both photopic and scotopic function by age 30 years. This retinal degeneration slow gene mutation may lead to the primary loss of both rod and cone photo-receptor function.

Adult↗
PubMed1994

Ocular manifestations in autosomal dominant retinitis pigmentosa with a Lys-296-Glu rhodopsin mutation at the retinal binding site.

A lysine to glutamic acid substitution at codon 296 in the rhodopsin gene has been reported in a family with autosomal dominant retinitis pigmentosa. This mutation is of particular functional interest as this lysine molecule is the binding site of 11-cis-retinal. The clinical features of a family with this mutation have not been reported previously. We examined 14 patients with autosomal dominant retinitis pigmentosa and a lysine-296-glutamic acid rhodopsin mutation. Four had detailed psychophysical and electrophysiological testing. Most affected subjects had severe disease with poor night vision from early life, and marked reduction of visual acuity and visual field by their early forties. Psychophysical testing showed no demonstrable rod function and severely reduced cone function in all patients tested.

Adolescent↗
PubMed1994

Further refinement of the location for autosomal dominant retinitis pigmentosa on chromosome 7p (RP9).

A form of autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 7p was recently reported by this laboratory, in a single large family from southeastern England. Further sampling of the family and the use a number of genetic markers from 7p have facilitated the construction of a series of multipoint linkage maps of the region with the most likely disease gene location. From this and haplotype data, the locus can now be placed between the markers D7S484 and D7S526, in an interval estimated to be 1.6-4 cM. Genetic distances between the markers previously reported to be linked to this region and those described in the recent whole-genome poly-CA map were estimated from data in this and other families. These data should assist in the construction of a physical map of the region and will help to identify candidate genes for the 7p adRP locus.

Chromosome Mapping↗
PubMed1993

A new locus for autosomal dominant retinitis pigmentosa on chromosome 7p.

Autosomal dominant retinitis pigmentosa (adRP) is known to result from mutations in two different retinal genes--rhodopsin and peripherin--while a third locus has been implicated by linkage data. However, families have been reported in which all three known loci have been excluded. We report linkage of adRP in one such family to two microsatellite markers on chromosome 7p. D7S435 has previously been localized to 7p13-15.1; D7S460, previously only localized to chromosome 7, maps to within 2 cM of D7S435 with a lod score of 12.15. Two point linkage analysis between these markers and adRP gave lod scores of 5.65 (theta = 0) and 4.19 (theta = 0.046) for D7S460 and D7S435, respectively. Multipoint analysis gave a maximum lod score of 8.22. These data strongly suggest a new adRP locus on chromosome 7p.

Base Sequence↗
PubMed1993

Autosomal dominant retinitis pigmentosa with apparent incomplete penetrance: a clinical, electrophysiological, psychophysical, and molecular genetic study.

Twenty five symptomatic individuals and six asymptomatic obligate gene carriers from four families with autosomal dominant retinitis pigmentosa (adRP) showing apparent incomplete penetrance have been studied. Symptomatic individuals from three families showed early onset of night blindness, non-recordable rod electroretinograms, and marked elevation of both rod and cone thresholds in all subjects tested. In the fourth family, there was more variation in the age of onset of night blindness and some symptomatic individuals showed well preserved rod and cone function in some retinal areas. All asymptomatic individuals tested had evidence of mild abnormalities of rod and cone function, indicating that these families show marked variation in expressivity rather than true non-penetrance of the adRP gene. No mutations of the rhodopsin or RDS genes were found in these families and the precise genetic mutation(s) remain to be identified.

Adolescent↗
PubMed1992

Exclusion of chromosome 6 and 8 locations in nonrhodopsin autosomal dominant retinitis pigmentosa families: further locus heterogeneity in adRP.

Genetic studies have revealed that 25 to 30% of autosomal dominant retinitis pigmentosa (adRP) families have mutations in the rhodopsin gene, while the remainder do not. More recently linkage data and mutation detection have demonstrated two further loci implicated in adRP, at an as yet unidentified gene on chromosome 8p and at the human gene homologue of the mouse Rds (Retinal Degeneration Slow) gene on chromosome 6p. We have previously reported exclusion of adRP from the rhodopsin locus on 3q in two large adRP families. We now report exclusion data for both families, on chromosomes 6 and 8, demonstrating that the adRP phenotype results from mutations in at least four locations.

Chromosome Mapping↗
PubMed1992

Molecular genetics of inherited retinal degenerations.

There has recently been substantial progress in categorizing the vast range of human retinal degeneration phenotypes. A molecular approach has assigned chromosomal locations for approximately a dozen such diseases and has identified four of the genes involved.

Albinism, Ocular↗
PubMed1992

A completed screen for mutations of the rhodopsin gene in a panel of patients with autosomal dominant retinitis pigmentosa.

Recently it has been demonstrated that some families with autosomal dominant retinitis pigmentosa (adRP) have mutations in the rhodopsin gene while others do not. Previously we have identified six such mutations in seven adRP families in this laboratory, one of which was previously described in US patients. We now present a completed screen of the rhodopsin gene in a panel of 39 adRP families, by a rapid screening technique which will be of use for routine diagnosis. Nine different mutations were ultimately found, in a total of twelve of the 39 families. These include the six previously identified mutations, in codons 68-71, 190, 211, 255, 296 and 347, two new ones in codons 53 and 106, and another mutation first identified in a single US patient, in codon 58. Thus approximately 30% of adRP families have 'Rhodopsin RP' while the remainder probably have a defect elsewhere in the genome. Of those families in which rhodopsin mutations have been found, four have been classified D type, three as sectorial RP and the remainder are of uncertain classification. All families excluded from chromosome 3q by linkage have been classified R type. These data suggest a correlation between clinical sub-classification and the underlying rhodopsin/non-rhodopsin heterogeneity.

Amino Acid Sequence↗
PubMed1992

Abnormal dark adaptation kinetics in autosomal dominant sector retinitis pigmentosa due to rod opsin mutation.

The time course of dark adaptation was measured in 10 subjects from three families with autosomal dominant sector retinitis pigmentosa (RP) due to mutations in the first exon of the rod opsin gene. In each subject cone adaptation and the early part of the recovery of rod sensitivity followed the normal time course, but the later phase of rod adaptation was markedly prolonged. The recovery of rod sensitivity is much slower than that reported in any other outer retinal dystrophy. Using a model based upon primate data of rod outer segment length and turnover, we have calculated that the delayed phase of the recovery of rod sensitivity in the RP patients tested following strong light adaptation could be due in part to formation of new disc membrane with its normal concentration of rhodopsin rather than in situ regeneration of photopigment.

Adolescent↗
PubMed1992

Recombination between rhodopsin and locus D3S47 (C17) in rhodopsin retinitis pigmentosa families.

Autosomal dominant retinitis pigmentosa (adRP) has shown linkage to the chromosome 3q marker C17 (D3S47) in two large adRP pedigrees known as TCDM1 and adRP3. On the basis of this evidence the rhodopsin gene, which also maps to 3q, was screened for mutations which segregated with the disease in adRP patients, and several have now been identified. However, we report that, as yet, no rhodopsin mutation has been found in the families first linked to C17. Since no highly informative marker system is available in the rhodopsin gene, it has not been possible to measure the genetic distance between rhodopsin and D3S47 accurately. We now present a linkage analysis between D3S47 and the rhodopsin locus (RHO) in five proven rhodopsin-retinitis pigmentosa (rhodopsin-RP) families, using the causative mutations as highly informative polymorphic markers. The distance, between RHO and D3S47, obtained by this analysis is theta = .12, with a lod score of 4.5. This contrast with peak lod scores between D3S47 and adRP of 6.1 at theta = .05 and 16.5 at theta = 0 in families adRP3 and TCDM1, respectively. These data would be consistent with the hypothesis that TCDM1 and ADRP3 represent a second adRP locus on chromosome 3q, closer to D3S47 than is the rhodopsin locus. This result shows that care must be taken when interpreting adRP exclusion data generated with probe C17 and that it is probably not a suitable marker for predictive genetic testing in all chromosome 3q-linked adRP families.

Chromosome Mapping↗