Cheryl Y. Gregory

Confirmation of the rod cGMP phosphodiesterase β subunit (PDEβ) nonsense mutation in affected rcd-1 Irish setters in the UK and development of a diagnostic test

Rodkone dysplasia type one (rcd-1) is an early onset inherited retinal dystrophy segregating in the Irish setter breed. It is classed as one of the autosomal recessive canine generalised Progressive Retinal Atrophies (PRA). The disease results in complete loss of photoreceptors by approximately one year of age. Levels of retinal cGMP are markedly elevated and of abnormal distribution in rod photoreceptors. Rod phosphodiesterase activity is absent and mRNA encoding the beta subunit (PDEB) of the holoenzyme is uniquely reduced in predegenerate retinae. Using retinae from normal, unrelated adult dogs we have PCR-amplified and sequenced the cDNA for PDEβ. The cDNA is almost identical to that recently described for the Irish setter in the USA apart from two translationally silent single nucleotide changes. Using carrier and affected setters from a UK breeding colony we have screened genomic DNA and can confirm the G to A transition in rcd-1 affected dogs at position 2420, creating an amber mutation in codon 80...

Phenotype of a British North Carolina macular dystrophy family linked to chromosome 6q

AIMS To document the phenotype of an autosomal dominant macular dystrophy diagnosed as having North Carolina macular dystrophy (NCMD) in this British family, and to verify that the disease locus corresponds with that of MCDR1 on chromosome 6q. METHODS 37 family members were examined and the phenotype characterised. DNA samples from the affected members, 19 unaffected and five spouses, were used to perform linkage analysis with six microsatellite marker loci situated within the MCDR1 region of chromosome 6q. RESULTS Every affected family member had lesions characteristic of NCMD, which developed early in life and usually remain stable thereafter. Although fundus changes are evident in the periphery, all tests revealed that functional loss is restricted to the macula. Some patients with large macular lesions had good visual acuity with fixation at the edge of the lesion at 5° eccentricity. Significant linkage to the MCDR1 locus on chromosome 6q was obtained with three marker loci, with a maximum lod score of 5.9 (q = 0.00) obtained with D6S249. CONCLUSION This family has the typical phenotype NCMD, and the causative gene was linked to the disease locus (MCDR1) on chromosome 6q. Early onset and localisation of the disease to the central macula allow specialisation of eccentric retina in some eyes with resultant good visual acuity.

GENETIC REFINEMENT OF THE CHROMOSOME-5Q LATTICE CORNEAL-DYSTROPHY TYPE-I LOCUS TO WITHIN A 2-CM INTERVAL

Lattice corneal dystrophy type I (LCDI) is a relatively common corneal dystrophy which can cause severe visual impairment. Recent studies have suggested a genetic localisation for the disease to chromosome 5q. Independent genetic linkage analysis in a six generation LCDI pedigree confirmed linkage to the 5q region bounded by marker loci IL9 and D5S436 suggesting genetic homogeneity. A maximum two point lod score of 7.51 (theta = 0.03) was obtained with marker D5S393. Multipoint and haplotype data positioned the disease between loci D5S393 and D5S396 corresponding to a genetic distance of 2cM, thus refining linkage sufficiently to allow for physical mapping of this disorder.

The role of molecular genetics in the prenatal diagnosis of retinal dystrophies

Inherited retinal dystrophies are important causes of incurable blindness in developed countries. Advances in molecular genetics promise significant improvements in their management. Immediate benefits of present knowledge are presymptomatic and prenatal diagnosis in selected cases. To study the predictive power of these techniques a simulated genetic risk estimation was undertaken in a cone-rod retinal dystrophy pedigree known to be linked to chromosome 19. Using data on five fully informative, flanking DNA markers, phenotype was correctly assigned with only a 2% probability of error. If the two most closely linked markers were found to be uninformative, this error probability remained unchanged. Using genetic risk calculations and direct mutation detection many retinal dystrophies could now be identified by prenatal diagnosis.

Molecular Genetic Studies of Retinal Dystrophies Principally Affecting the Macula

More than 3000 inherited disorders are known to afflict man. Amongst these, 372 distinct entities are associated with choroidoretinal dystrophies, 104 of which are solely ocular (1). For most, little information is as yet available on the underlying genetic or biological deficit. Developments in molecular genetics are improving this situation. Recently a number of retinal dystrophies have been assigned to refined chromosomal loci and in some cases specific gene mutations identified. Dystrophies which exclusively or principally affect the macular region of the human retina are an important subgroup. Characteristically there is earlier onset loss of central acuity with color vision deficits. These conditions contribute significantly to the incidence of blindness in developed countries such as the USA and UK, especially for onset of blindness in childhood (2). Since some macular diseases share similar histopathologic and clinical features, elucidation of the precise pathogenic mechanisms in selected examples may indirectly shed light on the pathogenesis of others. Therefore, with the aim of identifying genetic loci important in the pathogenesis of macular disease in general, a molecular genetic study was undertaken in seven pedigrees expressing different phenotypes that principally affect macular function.