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Biomedical subjects

C F Inglehearn

Publications and source records attributed to C F Inglehearn.

At least 19 recordsLinked to original sources
PubMed1998

Molecular genetics of human retinal dystrophies.

Retinal dystrophies are a heterogeneous group of diseases in which the retina degenerates, leading to either partial or complete blindness. The severe and clearly hereditary forms, retinitis pigmentosa (RP) and various macular degenerations, affect approximately 1 in 3000 people, but many more suffer from aging macular dystrophy in later life. Patients with RP present with narrowing visual fields and night blindness, while those with diseases of the macula lose central vision first. Even before the advent of molecular genetics it was evident that these were heterogeneous disorders, with wide variation in severity, mode of inheritance and phenotype. However, with the widespread application of linkage analysis and mutation detection techniques, a complex underlying pathology has now been revealed. In total, 66 distinct non-overlapping genes or gene loci have been implicated in the various forms of retinal dystrophy, with more being reported regularly in the literature. Within the category of non-syndromic RP alone there are at least 22 genes (and probably many more) involved, with further allelic heterogeneity arising from different mutations in the same gene. This complexity presents a problem for those involved in counselling patients, and also compounds the search for therapies. Nevertheless, several lines of research raise the hope of generic treatments applicable to all such patients, while the greater understanding of normal visual function that arises from genetic studies may open up new avenues for therapy.

Genes, Dominant↗
PubMed1998

A linkage survey of 20 dominant retinitis pigmentosa families: frequencies of the nine known loci and evidence for further heterogeneity.

Autosomal dominant retinitis pigmentosa (ADRP) is caused by mutations in two known genes, rhodopsin and peripherin/Rds, and seven loci identified only by linkage analysis. Rhodopsin and peripherin/Rds have been estimated to account for 20-31% and less than 5% of ADRP, respectively. No estimate of frequency has previously been possible for the remaining loci, since these can only be implicated when families are large enough for linkage analysis. We have carried out such analyses on 20 unrelated pedigrees with 11 or more meioses. Frequency estimates based on such a small sample provide only broad approximations, while the above estimations are based on mutation detection in much larger clinic based patient series. However, when markers are informative, linkage analysis cannot fail to detect disease causation at a locus, whereas mutation detection techniques might miss some mutations. Also diagnosing dominant RP from a family history taken in a genetic clinic may not be reliable. It is therefore interesting that 10 (50%) of the families tested have rhodopsin-RP, suggesting that, in large clearly dominant RP pedigrees, rhodopsin may account for a higher proportion of disease than had previously been suspected. Four (20%) map to chromosome 19q, implying that this is the second most common ADRP locus. One maps to chromosome 7p, one to 17p, and one to 17q, while none maps to 1cen, peripherin/Rds, 8q, or 7q. Three give exclusion of all of these loci, showing that while the majority of dominant RP maps to the known loci, a small proportion derives from loci yet to be identified.

Chromosome Mapping↗
PubMed1997

Analysis of a human gene homologous to rat ventral prostate.1 protein.

We report on the analysis of a human gene homologous to the rat ventral prostate.1 protein (RVP.1), which is transcriptionally induced in the regressing rat prostate after castration. EST database searching and Northern blotting reveal that this is one of at least four different members of a gene family in the human genome that produce transcripts of 3.4, 2.4, 1.9, and 1.2 kb, expressed in a wide range of tissues. Three other members of this gene family have already been mapped to chromosomes 7q, 17p, and 22q and reported either as anonymous ESTs or as full-length clones. We have now characterized a fourth member (assigned the gene now characterized a fourth member (assigned the gene name C7orf1 by GDB) and localized it also to chromosome 7q. C7orf1 is almost identical over much of its length to the reported ORF of RVP.1 while the other family members are more divergent from RVP.1. The genomic sequence of C7orf1 is intron-less, is spanned by a CpG low-methylation island, and has two noncoding, nonpolymorphic STR regions immediately adjacent to the open reading frame, one 5' and one 3'. The presence of a NotI restriction site in the coding sequence results in a deficiency in the IMAGE cDNA libraries, as a result of which the 3' end of the gene is not in the EST databases. The putative 220-amino-acid protein shows 89% identity to the amino terminus of rat RVP.1. Like rat RVP.1, it has four hydrophobic potential membrane-spanning regions, but it lacks 60 amino acid residues at its carboxyl terminus relative to rat RVP.1. Nevertheless, gene-specific primers from this transcript amplified a product in human cDNAs from several different tissues; its size corresponds to the 1.2-kb transcript seen on a Northern blot, and identical ESTs from several different tissues exist in the databases. It therefore seems likely that C7orf1 is the closest human homologue of rat RVP.1.

Amino Acid Sequence↗
PubMed1997

Exclusion of CAG repeat expansion as the cause of disease in autosomal dominant retinitis pigmentosa families.

The involvement of genes with expanded tracts of (CAG)n in some neurodegenerative diseases is well established. Whether genes containing these motifs could also have a role in degenerative diseases affecting the retina, which is also neural in origin, is unknown. We investigated (CAG)n expansions as a cause of disease in a panel of eight autosomal dominant retinitis pigmentosa (ADRP) pedigrees, including families known to map to the RP9, RP11, and RP13 loci, using the technique known as "repeat expansion detection" (RED). An expansion was detected in one of the unlinked families, but it did not segregate with the disease and was thus nonpathogenic. Expansions were not detected in any other families. In conclusion, expanded (CAG)n repeats are not the cause of disease in the families we have studied, but given the high level of heterogeneity in RP and in retinal degenerations in general they remain strong candidates for involvement in other forms of retinal dystrophy.

Female↗
PubMed1996

Mutations and polymorphisms in the human peripherin-RDS gene and their involvement in inherited retinal degeneration.

The RDS gene codes for the protein peripherin-RDS, which is an integral membrane glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It is thought to function as a structural protein involved in the maintenance of the flattened form of the disc lamellae. The RDS gene has been implicated in the mouse phenotype retinal degeneration slow, and mutations in the human homologue are now known to be associated with both central and peripheral retinal degenerations. In all, 43 sequence variants have been described in the human gene, including 30 missense mutations, two single base substitutions producing termination codons, 7 small in-frame deletions, and 4 insertion/ deletion events, which break the reading frame. Of these, 39 are associated with retinal phenotypes, which can be grouped into four broad categories: dominant retinitis pigmentosa, progressive macular degeneration, digenic RP, and pattern dystrophies. The mutations underlying dominant RP and severe macular degeneration are largely missense or small in-frame deletions in a large intradiscal loop between the third and fourth transmembrane domains. In contrast, those associated with the milder pattern phenotypes or with digenic RP are scattered more evenly through the gene and are often nonsense mutations. This observation correlates with the hypothesis that the large loop is an important site of interaction between RDS molecules and other protein components in the disc.

Animals↗
PubMed1996

Localization of a novel t(1;7) translocation associated with Wilms' tumor predisposition and skeletal abnormalities.

Cytogenetic analysis of predisposition syndromes has played a critical role in the elucidation of the genetics of Wilms' tumor (WT). Therefore, we became interested in a patient who presented with a WT and a nephrogenic rest in the contralateral kidney (suggestive of a predisposition) and a de novo t(1;7)(q42;p15) constitutional translocation as the only visible cytogenetic abnormality. He also had bilateral radial aplasia and other skeletal abnormalities, but there was no manifestation of any syndrome previously associated with WT. In the tumor, the translocation was retained, and the other 7p region was lost by the formation of an isochromosome i(7q). Here, we report the localization of the chromosome 7 breakpoint within a yeast artificial chromosome (YAC) contig by using fluorescence in situ hybridization (FISH), localizing the breakpoint between markers sWSS355 and sWSS1449. A number of YACs span the breakpoint and, thus, contain the region that is disrupted by the translocation. This may represent the site of a novel tumor suppressor gene that is involved in WT and also in normal renal development.

Bone and Bones↗
PubMed1996

A new family linked to the RP13 locus for autosomal dominant retinitis pigmentosa on distal 17p.

A form of autosomal dominant retinitis pigmentosa (ADRP) mapping to chromosome 17p has been reported in a single large South African family. We now report a new family with severe early onset ADRP which maps to 17p. Linkage and haplotype analysis in this family places the ADRP locus in the 5 cM interval between markers AFMc024za5 and D17S1845, confirming the data obtained in the South African family. The discovery of a second 17p linked family may imply that this is one of the more common loci for dominant RP. In addition, the confirmation of an RP diagnosis at this locus is of interest since loci for a dominant cone dystrophy and Leber's congenital amaurosis (LCA1) have recently been linked to the same markers. While the cone dystrophy locus may be allelic with RP, our data and that of Goliath et al show that distinct genes are responsible for dominant RP and Leber's congenital amaurosis on chromosome 17p.

Chromosomes, Human, Pair 17↗
PubMed1996

Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11) and association with a unique bimodal expressivity phenotype.

Retinitis pigmentosa (RP) is the name given to a heterogeneous group of retinal degenerations mapping to at least 16 loci. The autosomal dominant form (ARP), accounting for approximately 25% of cases, can be caused by mutations in two genes, rhodopsin and peripherin/RDS, and by at least six other loci identified by linkage analysis. The RP11 locus for adRP has previously been mapped to chromosome 19q13.4 in a large English family. This linkage has been independently confirmed in a Japanese family, and we now report three additional unrelated linked U.K. families, suggesting that this is a major locus for RP. Linkage analysis in the U.K. families refines the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibit incomplete penetrance; some obligate gene carriers remain asymptomatic throughout their lives, whereas symptomatic individuals experience night blindness and visual field loss in their teens and are generally registered as blind by their 30s. This "bimodal expressivity" contrasts with the variable-expressivity RP mapping to chromosome 7p (RP9) in another family, which has implications for diagnosis and counseling of RP11 families. These results may also imply that a proportion of sporadic RP, previously assumed to be recessive, might result from mutations at this locus.

Chromosome Mapping↗
PubMed1995

Regional assignment of 30 expressed sequence tags on human chromosome 7 using a somatic cell hybrid panel.

The regional assignments of 30 expressed sequence tags (ESTs) on human chromosome 7 were determined by studying the segregation of their PCR-amplified products in a panel of mouse somatic cell hybrids. ESTs are important molecular landmarks for physical mapping and can be considered as tags to candidate genes for genetically linked human inherited diseases. These results contribute further potential gene sequences to the transcriptional map of chromosome 7.

Animals↗
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↗