Splicing Mutations of 54-bp Exons in the COL11A1 Gene Cause Marshall Syndrome, but Other Mutations Cause Overlapping Marshall/Stickler Phenotypes

Abstract

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Molecular genetics of rhegmatogenous retinal detachment

“…21 We suspect that mutations in this gene interfere with this regulation, resulting in thicker than normal fibrils and this is reflected in the appearance of the lamellae of the vitreous. Similar mutations in COL11A1 22,23 have also been described in Marshall syndrome (see below). However the vitreous Eye: Cambridge Ophthalmological Symposium appearance of affected individuals was not described so that comparisons with type 2 Stickler syndrome are difficult to make.…”

“…Two reports have characterised mutations of ␣1(XI) collagen in cases of Marshall syndrome. 22,23 These have associated skipping of 54-bp exons of COL11A1 with the syndrome. Other mutations in the same gene were said to result in mixed Marshall/Stickler phenotypes.…”

Collagen 11a1 is indirectly activated by lymphocyte enhancer-binding factor 1 (Lef1) and negatively regulates osteoblast maturation

“…Collagen 11a1 is mutated in Marshall and Stickler syndromes (Snead et al, 1996;Griffith et al, 1998;Meisler et al, 1998;Annunen et al, 1999;Martin et al, 1999;Snead and Yates, 1999). Patients with Marshall syndrome exhibit short stature and bony overgrowths on the skull (Stratton et al, 1991;Meisler et al, 1998), suggesting a role for Col11a1 in controlling bone mineralization.…”

“…Mutations in Col11a1 cause Marshall and type II Stickler syndromes Annunen et al, 1999). Marshall syndrome is an autosomal dominant inherited disease characterized by short stature, nearsightedness, hearing loss, flattened facial features, thickened calvarium and intercranial ossifications.…”

“…Both syndromes occasionally present with cleft palate and patients frequently develop early osteoarthritis (Olsen, 1995;Snead and Yates, 1999;Rodriguez et al, 2004;Jakkula et al, 2005). Whether Marshall and Stickler syndromes are variants of the same disease or separate syndromes is controversial, but it is apparent that they are very similar and many patients display symptoms of both diseases (Winter et al, 1983;Ayme and Preus, 1984;Stratton et al, 1991;Annunen et al, 1999).…”