Stickler syndrome: further mutations in COL11A1 and evidence for additional locus heterogeneity

Abstract

Stickler syndrome (hereditary arthro-ophthalmopathy) is a dominantly inherited connective tissue disorder with ocular, oro-facial, auditory and skeletal manifestations. It is genetically and phenotypically heterogeneous with the majority of families having mutations in the gene encoding type II collagen (COL2A1) and exhibiting a characteristic 'membranous' or type 1 vitreous phenotype. More recently a novel mutation in the gene encoding the α1 chain of type XI collagen (COL11A1) was reported in a Stickler syndrome pedigree with a different 'beaded' or type 2 vitreous phenotype. In the present study five more families with the type 2 vitreous phenotype were examined for linkage to four candidate genes: COL2A1, COL5A2, COL11A1 and COL11A2. Two families were linked to COL11A1 and sequencing identified mutations resulting in shortened α1(XI) collagen chains, one via exon skipping and the other via a multiexon deletion. One of the families showed weak linkage to COL5A2 but sequencing the open reading frame failed to identify a mutation. In the remaining two families all four loci were excluded by linkage analysis. These data confirm that mutations in COL11A1 cause Stickler syndrome with the type 2 vitreous phenotype and also reveal further locus heterogeneity.

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.…”

Molecular genetics of rhegmatogenous retinal detachment

“…19 Analysis of two other families found an exon skipping mutation and a large multiexon deletion in COL11A1. 20 All three of these families had a vitreous with a beaded appearance to its structure (Figure 2). Analysis of two sporadic cases with an identical phenotype also found mutations in the COL11A1 gene (unpublished results).…”

“…Other families are not linked to either COL2A1 or COL11A1 and so at least one other locus for Stickler syndrome exists. 20,24 Another type XI collagen gene, COL11A2, is not expressed in the eye and mutations in it result in a non-ocular chondrodysplasia phenotype (MIM 184840).…”

The Stickler syndrome: Genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1

“…32 Stickler syndrome is genetically heterogeneous as mutations in COL2A1 (12q13) account for only about 70% of reported Stickler families. [33][34][35][36][37] Among the remaining families, linkage to COL11A1 (1p21) [37][38][39] or a mutation in the COL11A2 (6p21) gene locus of type XI collagen in a nonocular form of Stickler syndrome has been reported. 37,40 Further genetic heterogeneity is likely, as linkage to the three Stickler-related genes has been excluded in some affected families.…”