Clinical and molecular characterization of a family with autosomal recessive cornea plana.

BACKGROUND: Autosomal recessive cornea plana is characterized by a flattened corneal surface associated with hyperopia and various anterior segment abnormalities. Mutations have been detected in the keratocan gene (KERA), a member of the small leucine-rich proteoglycan family. OBJECTIVE: To clinically and molecularly characterize a consanguineous family of Hispanic origin in which 3 individuals are affected with cornea plana. METHODS: Clinical ophthalmic examination, including corneal topography and axial eye length measurement, was performed on 7 family members. Molecular analysis of KERA was performed on DNA from each family member who had been examined. RESULTS: All 3 affected individuals showed extreme flattening of the cornea (< 36 diopters [D]), normal axial eye lengths, and hyperopia greater than 6.25 D (spherical equivalent). Anterior segment abnormalities included scleralization of the cornea and central iris strands to the corneal endothelium. Affected individuals were homozygous for a novel mutation in KERA. The sequence change was found in exon 2, which results in an asparagine to aspartic acid change at codon 131. This amino acid change occurs within a highly conserved leucine-rich repeat of keratocan. CONCLUSIONS: The cause of disease in this family is likely to be a mutation in exon 2 of KERA. Other mutations in KERA known to cause cornea plana also fall within the region encoding the leucine-rich repeat motifs and are predicted to affect the tertiary structure of the protein. CLINICAL RELEVANCE: This is the first report of the identification of a mutation within KERA in a family of Hispanic origin with autosomal recessive cornea plana. Although the vast majority of cases of cornea plana are in individuals of Finnish descent, this report demonstrates the occurrence of the disease in other populations.

Mutations in the CACNA1F and NYX genes in British CSNBX families.

X-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX.

Exclusion of four candidate genes, KHDRBS2, PTP4A1, KIAA1411 and OGFRL1, as causative of autosomal recessive retinitis pigmentosa.

To identify the disease gene in 6 Spanish families with autosomal recessive retinitis pigmentosa linked to the RP25 locus, mutation screening of 4 candidate genes, KHDRBS2, PTP4A1, KIAA1411 and OGFRL1, was undertaken based on their expression or functional relevance to the retina. Twenty-six single nucleotide polymorphisms were identified, of which 14 were novel. Even though no pathological mutations were detected, these genes however remain as good candidates for other retinal degenerations mapping to the same chromosomal region.

Genomic organisation and alternative splicing of human RIM1, a gene implicated in autosomal dominant cone-rod dystrophy (CORD7).

A mutation has been identified in the Rab3A-interacting molecule (RIM1) gene in CORD7, an autosomal dominant cone-rod dystrophy that localises to chromosome 6q14. The G to A point mutation results in an Arg844His substitution in the C(2)A domain of the protein that segregates with disease. This mutation is absent in over 200 control chromosomes, indicating that it is not a common polymorphism, and the almost complete sequence conservation of the C(2)A domain between human and rat RIM1 is consistent with a disease role for the change. RIM1 is expressed in brain and photoreceptors of the retina where it is localised to the pre-synaptic ribbons in ribbon synapses. The RIM1 gene is composed of at least 35 exons, spans 577 kb of genomic DNA, and encodes a protein of up to 1693 residues. The transcript shows extensive alternative splicing involving exons 17, 21-26 and 28-30.

Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.

Retinitis pigmentosa (RP), the commonest form of inherited retinal dystrophies is a clinically and genetically heterogeneous disorder. It is characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of peripheral visual field. RP is inherited either in an autosomal dominant, autosomal recessive or X-linked mode. A locus (RP18) for autosomal dominant RP was previously mapped by linkage analysis in two large pedigrees to chromosome 1p13-q21. The human HPRP3 gene, the orthologue of the yeast pre-mRNA splicing factor (PRP3), localizes within the RP18 disease interval. The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families. So far, two different missense mutations in two English, a Danish family and in three RP individuals have been identified. Both mutations are clustered within a two-codon stretch in the 11th exon of the HPRP3 gene. Interestingly, one of the mutations (T494M) is seen repeatedly in apparently unlinked families raising the possibility of a mutation hot spot. This has been confirmed by haplotype analysis using SNPs spanning the HPRP3 gene region supporting multiple origins of the mutation. The altered HPRP3 amino acids, which are highly conserved in all known HPRP3 orthologues, indicate a major function of that domain in the splicing process. The identification of mutations in a third pre-mRNA splicing factor gene further highlights a novel mechanism of photoreceptor degeneration due to defects in the splicing process.