Allelic and locus heterogeneity in autosomal recessive gelatinous drop-like corneal dystrophy

Abstract

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive disease characterized by the deposition of amyloid beneath the corneal epithelium and by severely impaired visual acuity leading to blindness. Although gelatinous corneal dystrophy has previously been mapped to chromosome 1p and seems to be associated with mutations in the M1S1 gene, molecular genetic studies have been limited to Japanese patients. To investigate the cause of GDLD in patients with diverse ethnic backgrounds, we performed linkage analyses in eight unrelated GDLD families from India, USA, Europe, and Tunisia. In seven of these families, the disease locus mapped to a 16-cM interval on the short arm of chromosome 1 between markers D1S519 and D1S2835, a region including the M1S1 gene. In addition, a 1.2-kb fragment containing the entire coding region of M1S1 gene was sequenced in affected individuals. Seven novel mutations (M1R, 8-bp ins., Q118 E, V194 E, C119 S, 870delC, and 1117delA) were identified in six families and two unrelated individuals. No sequence abnormalities were detected in a single family in which the GDLD locus was also excluded from the M1S1 region by linkage analysis. These findings demonstrate allelic and locus heterogeneity for GDLD.

Gelatinous drop-like corneal dystrophy in a child with developmental delay: clinicopathological features and exclusion of the M1S1 gene

“…9,10,12,13,15,17,23 Most subjects studied have been of Japanese or Indian origin, although Tunisian, American and European cases have also been reported. 19, 24 Ren et al 12 were able to exclude linkage to M1S1 in a single large Caucasian pedigree, confirming locus heterogeneity. Lactoferrin, a promising candidate gene could also be excluded by linkage analysis in this family.…”

“…11 Mutations in the BIGH3 gene have been considered unlikely as a cause of GDLD, 25 since of the wide variety of keratoepithelin mutations that have been documented, all exhibit autosomal dominant transmission. 12 The affected proband was homozygous at three polymorphic sites in the M1S1 gene. One of these was in the 5 0 UTR and thus considered unlikely to have functional consequences.…”

“…8 The disorder has been mapped to chromosome 1p and associated, in most, but not all cases with mutations in the M1S1 gene. [9][10][11][12][13][14][15][16][17] Yoshida et al 18 reported that the Q118X mutation of the M1S1 gene could produce either a gelatinous drop-like region or band-shaped opacities.…”

TGFBI gene mutations in corneal dystrophies

“…All affected individuals had the Arg124Cys mutation and no detectable changes in the M1S1 gene, which is responsible for GDLD. Despite this, it may not be possible to rule out the coexistence of GDLD in these patients, because there is evidence for genetic heterogeneity in GDLD and M1S1 is not the only locus for this disorder [Ren et al, 2002]. Another deviation from the LCD type I phenotype in association with the Arg124Cys mutation was observed in a Japanese patient, who had a diffuse corneal opacification, without linear opacities [Yoshida et al, 2004].…”

Familial Gelatinous Drop-Like Corneal Dystrophy Caused by a Novel Nonsense TACSTD2 Mutation

“…1,2 Only a few cases have been reported in patients from Europe and North America. 3,4 Clinical manifestations appear during the first decade of life with axial, bilateral, elevated, mulberry-like gelatinous corneal lesions containing amyloid deposits located in the subepithelium and anterior stroma of the cornea. During the early stages of the disease, white-yellow nodular lesions are identified in the central corneal subepithelium.…”