ABSTRACT
Open-angle glaucoma (POAG) is a highly prevalent cause of visual impairment. Six families grouping 71 living patients affected with juvenile-onset and middle-age POAG (age at diagnosis ranging from 10 to 65 years) were linked to the GLC1A locus. All patients carried a mutation of an evolutionarily conserved asparagine residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain, which is encoded by the third exon of the GLC1A gene. The N480K mutation was also identified in 14 unaffected carriers who are at high risk of developing POAG. Although four of the families had ancestors identified in Northern France, the pedigrees could not be interconnected by genealogical investigation. However, haplotype analysis indicated that all the carriers had inherited the N480K mutation from the same founder. Screening of a selected set of 67 POAG patients who originated from Northern France and underwent trabeculectomy before the age of 50, detected one patient with the N480K mutation associated with the same disease haplotype already characterized in the 6 families. This group of 72 POAG patients is the largest one having a GLC1A mutation in common and provides a unique tool to investigate the factors influencing the variable expressivity of the GLC1A gene.
Subject(s)
Eye Proteins/genetics , Founder Effect , Genetic Linkage , Glaucoma, Open-Angle/genetics , Glycoproteins/genetics , Adolescent , Adult , Age of Onset , Aged , Child , Cytoskeletal Proteins , DNA Mutational Analysis , France , Gene Expression Regulation , Glaucoma, Open-Angle/diagnosis , Haplotypes , Heterozygote , Humans , Middle Aged , Pedigree , Point MutationABSTRACT
The entire nucleotide sequence between coordinates 89.5 and 100% of the Ad 2 DNA genome has been determined using the Maxam and Gilbert method. This sequence of 3766 bp contains information relative to the carboxylic end of the fiber protein and to the entire E4 region. The position within the nucleotide sequence of various open reading frames and of several consensus splicing sequences was correlated with the location by EM and Sl digestion of the E4 mRNA. This correlation allows to suggest an additional splicing event in the maturation process of i or f mRNA and to deduce the structure of most E4 mRNA. The aminoacid sequences of the corresponding proteins are deduced allowing the location of several glycosylation sites. The presence of several open reading frames with a substantial coding capacity permits to postulate on the existence of additional genes located at the 3' end of the fiber gene and the 3' end of the E4 region. The existence of these putative additional genes might explain that termination of transcription is several hundred nucleotides beyond the main known poly A addition sites of the L5 and E4 regions.
