Marshall Syndrome Associated with a Splicing Defect at the COL11A1 Locus

Abstract

Marshall syndrome is a rare, autosomal dominant skeletal dysplasia that is phenotypically similar to the more common disorder Stickler syndrome. For a large kindred with Marshall syndrome, we demonstrate a splice-donor-site mutation in the COL11A1 gene that cosegregates with the phenotype. The G+1-->A transition causes in-frame skipping of a 54-bp exon and deletes amino acids 726-743 from the major triple-helical domain of the alpha1(XI) collagen polypeptide. The data support the hypothesis that the alpha1(XI) collagen polypeptide has an important role in skeletal morphogenesis that extends beyond its contribution to structural integrity of the cartilage extracellular matrix. Our results also demonstrate allelism of Marshall syndrome with the subset of Stickler syndrome families associated with COL11A1 mutations.

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.…”

Avaliação genética e oftalmológica de pacientes com síndrome de Stickler tipo II

“…Porém, a dificuldade no diagnóstico diferencial com outras alterações genéticas como a síndrome de Marshall ou fenótipo Marshall/ Stickler (21) , síndrome de Wagner (20,23) , alta miopia familial (26) , subestima o número de pacientes com síndrome de Stickler.…”

“…Devido às várias mutações descritas na literatura, novos genes provavelmente relacionados à SS e a dificuldade clínica no diagnóstico diferencial, muitos profissionais médicos não fazem o diagnóstico correto dessa síndrome (7)(8)(20)(21)(22)(23)(24) .…”