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K. Paunescu, M.N. Preising, C. Friedburg, T. Rosenberg, B. Lorenz; Variation of Phenotype in Patients With Compound Heterozygous Mutations of RetGC1 Depending on the Affected Domains . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5802.
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To compare the phenotype of homozygous or compound heterozygous mutations in the catalytic domain of retinal guanylate cyclase 1 (RetGC1) with that of compound heterozygous mutations, in the catalytic domain on one allele and in the kinase or extra cellular domain on the second allele. RetGC1 mutations are usually considered to result in a severe congenital form of retinal dystrophy (Leber Congenital Amaurosis type 1, LCA1). A compound heterozygous genotype may lead to either LCA or cone–rod dystrophies depending on the domains affected. Some parents of patients with LCA due to mutations of RetGC1 who are single heterozygous for the underlying alleles have been reported to show a subtle phenotype on electrophysiological examination.
Complete ophthalmological investigation including fundus photography, Ganzfeld–ERG, Goldmann kinetic perimetry, fundus autofluorescence and OCT were carried out in patients with Early Onset Retinal Dystrophy including those with a milder phenotype. Screening for mutations was performed by Single Strand Conformation Polymorphism (SSCP) analysis and direct sequencing.
Two patients, one homozygous, and one compound heterozygous for mutations inside the catalytic domain, presented with severe LCA. Clinically, both had nystagmus, light perception, and pale optic discs. In contrast, two patients had a significantly milder phenotype: A 4 year old girl carried a deletion in the catalytic and a missense mutation in the extra cellular domain. The second patient showed two missense mutations, one in the catalytic, and one in the kinase domain. In childhood, both patients showed nystagmus since infancy, low visual acuity of about 0.1, hyperopia, slight RPE mottling and no bone spicule or other significant pigmentary changes. Ganzfeld–ERG responses were absent. In the older patient, visual acuity and peripheral visual fields remained more or less unchanged up to the age of 43 years.
The phenotype in patients with compound heterozygous mutations indicates a complex functional interaction of the domains of RetGC1. Compound heterozygous mutations of the catalytic domain and the extracellular or kinase domain lead to a significant but milder phenotype than LCA, while LCA can be predicted when both mutations reside inside the catalytic domain.
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