Founder effect in GLC1A‐linked familial open‐angle glaucoma in Northern France

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.

Myocilin mutations in a population-based sample of cases with open-angle glaucoma: the Rotterdam Study

“…The Asn480Lys mutation is situated near a casein kinase II site and causes a change in charge in the local residue and a gain of α-helix in the structural conformation of the MYOC protein [24]. A POAG pedigree segregating this mutation was previously described by Adam et al [1,4].…”

“…These persons were screened for the presence or absence of the mutation by direct sequencing. To investigate the possibility of a founder effect with the patients described by Brézin et al [4], the alleles of four markers in the region of the disease gene were compared between these patients and the patients of our family, P26333. The markers D1S2851, D1S242, D1S218 and D1S1165 were tested.…”

Regulation of human myocilin/TIGR gene transcription in trabecular meshwork cells and astrocytes: role of upstream stimulatory factor

“…Stone et al (Stone et al 1997) identi®ed three mutations in the gene for MYOC/TIGR, which lies within the interval on chromosome 1 that was originally associated with juvenile open angle-glaucoma (GLC1A) (Shef®eld et al 1993;Richards et al 1994;Wiggs et al 1994). Subsequently, mutations in the same gene of patients with GLC1A-linked juvenile open-angle glaucoma were also reported by other researchers (Adam et al 1997;Kee & Ahn 1997;Stoilova et al 1997;Suzuki et al 1997;Brezin et al 1998;Mansergh et al 1998;Michels-Rautenstrauss et al 1998). Juvenile open-angle glaucoma refers to a subset of POAG that has an earlier age of onset, a highly penetrant mode of inheritance and is usually associated with a high IOP requiring early surgical treatment (Wiggs et al 1995;Johnson et al 1996).…”

Glaucoma phenotype in a large Swiss pedigree with the myocilin Gly367Arg mutation

“…The age-related penetrance of 50% at 30 and nearly 80% at 40 is comparable to other MYOC mutations, for example, Cys433Arg and Asn480Lys. 24,25 So far, all reported MYOC mutations have incomplete penetrance at 30, with Thr377Met resulting in the highest 26 and Gln368STOP in the lowest 22,27 age of onset.…”