Dorothy Trump

Mutations in the Myosin VIIA Gene Cause a Wide Phenotypic Spectrum, Including Atypical Usher Syndrome

This work was supported by the Medical Research Council (U.K.), Defeating Deafness—the Hearing Research Trust, and SENSE and by European Community grant CT96-1324. C.H. acknowledges support from the British Retinitis Pigmentosa Society and the Birmingham Eye Foundation.

Molecular pathology of X linked retinoschisis: mutations interfere with retinoschisin secretion and oligomerisation

Background/aim: X linked retinoschisis (XLRS) is caused by mutations in RS1 which encodes the discoidin domain protein retinoschisin, secreted by photoreceptors and bipolar cells. Missense mutations occur throughout the gene and some of these are known to interfere with protein secretion. This study was designed to investigate the functional consequences of missense mutations at different locations in retinoschisin. Methods and results: The authors developed a structural model of the retinoschisin discoidin domain and used this to predict the effects of missense mutations. They expressed disease associated mutations and found that those affecting conserved residues prevented retinoschisin secretion. Most of the remaining mutations cluster within a series of loops on the surface of the β barrel structure and do not interfere with secretion, suggesting this region may be a ligand binding site. They also demonstrated that wild type retinoschisin octamerises and associates with the cell surface. A subgroup of secreted mutations reduce oligomerisation (C59S, C219G, C223R). Conclusions: It is suggested that there are three different molecular mechanisms which lead to XLRS: mutations interfering with secretion, mutations interfering with oligomerisation, and mutations that allow secretion and oligomerisation but interfere with retinoschisin function. The authors conclude that binding of oligomerised retinoschisin at the cell surface is important in its presumed role in cell adhesion.

Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG

Intensity-series rod and cone ERGs were recorded in 19 patients with XLRS and 26 control eyes. All patients were examined by one ophthalmologist and diagnosed on the basis of fundus appearance and evidence of the disease in other males in the same family. Mutations in the XLRS1 gene have been identified in 15 of the patients. Dark-adapted ERGs were significantly different from controls for all test conditions and for both a-wave and b-wave responses. Abnormalities were detectable in all patients but there was considerable variation in the severity of abnormality. One third of the patients had the dark-adapted `negative-wave response typically associated with inner retinal disorder, but about one third showed only mild depression of the b-wave while the remainder had abnormally low a-waves in addition to depressed b-waves. Light-adapted responses were also affected and both a-wave and b-wave responses differed significantly from controls, but the `negative-wave response was not seen in any patient. The severity of the ERG abnormality did not correlate with the classification of fundus appearance or patient age suggesting that retinal function is relatively stable throughout life. The severity of ERG abnormalities did not correlate with the type of mutation and responses could differ between affected males within the same family. These results indicate considerable heterogeneity of ERG response without clinical, age or genetic correlate. The abnormal a-wave responses indicate that photoreceptor as well as inner retinal layer function may be affected in XLRS, at least in some patients.

Genotype-phenotype correlation in British families with X linked congenital stationary night blindness.

Aim: To correlate the phenotype of X linked congenital stationary night blindness (CSNBX) with genotype. Methods: 11 CSNB families were diagnosed with the X linked form of the disease by clinical evaluation and mutation detection in either the NYX or CACNA1F gene. Phenotype of the CSNBX patients was defined by clinical examination, psychophysical, and standardised electrophysiological testing. Results: Comprehensive mutation screening identified NYX gene mutations in eight families and CACNA1F gene mutations in three families. Electrophysiological and psychophysical evidence of a functioning but impaired rod system was present in subjects from each genotype group, although the responses tended to be more severely affected in subjects with NYX gene mutations. Scotopic oscillatory potentials were absent in all subjects with NYX gene mutations while subnormal OFF responses were specific to subjects with CACNA1F gene mutations. Conclusions: NYX gene mutations were a more frequent cause of CSNBX than CACNA1F gene mutations in the 11 British families studied. As evidence of a functioning rod system was identified in the majority of subjects tested, the clinical phenotypes “complete” and “incomplete” do not correlate with genotype. Instead, electrophysiological indicators of inner retinal function, specifically the characteristics of scotopic oscillatory potentials, 30 Hz flicker and the OFF response, may prove more discriminatory.

A comparison of ERG abnormalities in XLRS and XLCSNB

Dark and light adapted ERGs were recorded in 19 patients with XLRS and in 15 patients with CSNB. Patients were assigned to clinical groups after identification of mutations in the RS1 (16 patients), NYX (11 patients) and CACNA1F (4 patients) genes causing XLRS, complete CSNB and incomplete CSNB, respectively. ERG responses were compared with those of 26 healthy volunteers. Rod responses were most severely affected in patients in the NYX group but a rod-generated b-wave could be identified in the majority of patients in this group. Rod responses were less severely affected in the CACNA1F and RS1 groups and ERGs did not differ significantly between these two groups. Cone reponses were largely unaffected in the NYX group but were abnormal in the RS1 and especially CACNA1F groups. The ERG results suggest that the RS1 and CACNA1F gene products have comparable functional consequences and that all three genes may affect multiple retinal sites.

Refinement of the NHS locus on chromosome Xp22.13 and analysis of five candidate genes.

Nance-Horan syndrome (NHS) is an X-linked condition characterised by congenital cataracts, dental abnormalities, dysmorphic features, and mental retardation in some cases. Previous studies have mapped the disease gene to a 2u2009cM interval on Xp22.2 between DXS43 and DXS999. We report additional linkage data resulting from the analysis of eleven independent NHS families. A maximum lod score of 9.94 (θ=0.00) was obtained at the RS1 locus and a recombination with locus DXS1195 on the telomeric side was observed in two families, thus refining the location of the gene to an interval of around 1 Mb on Xp22.13. Direct sequencing or SSCP analysis of the coding exons of five genes (SCML1, SCML2, STK9, RS1 and PPEF1), considered as candidate genes on the basis of their location in the critical interval, failed to detect any mutation in 12 unrelated NHS patients, thus making it highly unlikely that these genes are implicated in NHS.

Exclusion of RAI2 as the causative gene for Nance-Horan syndrome

Abstract Nance-Horan syndrome (NHS) is an X-linked condition characterised by congenital cataracts, microphthalmia and/or microcornea, unusual dental morphology, dysmorphic facial features, and developmental delay in some cases. Recent linkage studies have mapped the NHS disease gene to a 3.5-cM interval on Xp22.2 between DXS1053 and DXS443. We previously identified a human homologue of a mouse retinoic-acid-induced gene (RAI2) within the NHS critical flanking interval and have tested the gene as a candidate for Nance-Horan syndrome in nine NHS-affected families. Direct sequencing of the RAI2 gene and predicted promoter region has revealed no mutations in the families screened; RAI2 is therefore unlikely to be associated with NHS.

Temperature sensitive oculocutaneous albinism associated with missense changes in the tyrosinase gene.

Oculocutaneous albinism (OCA) describes a group of autosomal recessive disorders characterised by reduced or absent pigmentation of the eye, skin, and hair as a result of a congenital reduction in melanin synthesis. Additional findings in the eye include decreased visual acuity, nystagmus, iris transillumination, hypopigmentation of the uveal tract and retinal pigment epithelium, foveal hypoplasia, and abnormal decussation of the optic nerve fibres at the optic chiasm leading to a lack of binocular vision.1,2 Type I OCA results from mutations in the tyrosinase gene and leads to either total absence of tyrosinase activity (OCA Ia) associated with absence of pigmentation (“tyrosinase negative”), or a marked reduction in tyrosine activity (OCA Ib) associated with reduced pigmentation (“tyrosinase positive” or “yellow albinism”). We report a new case of the rare variant temperature sensitive albinism and our identification of missense mutations in the tyrosinase gene, not previously found in this form of albinism.nnThe patient, a 31 …