Br J Ophthalmol 2000;84:364-371
( April )
COL2A1 exon 2 mutations: relevance to the Stickler and Wagner
syndromes
Allan J Richardsa, Sam Martina, John R W Yatesb, John D Scottc, David M Baguleyd, F Michael Popee, Martin P Sneadc
a MRC Connective
Tissue Genetics Group, University of Cambridge, Department of
Pathology, Cambridge CB2 1QP, b Department of Medical Genetics, University of
Cambridge, c Vitreoretinal
Service, Department of Ophthalmology, d Department
of Audiology, Addenbrooke's Hospital, Hills Road, Cambridge CB2
2QQ, e Institute of Medical
Genetics, University Hospital of Wales, Heath Park, Cardiff CF4
4XN
Correspondence to: Martin P Snead,
Vitreoretinal Service, Addenbrooke's Hospital, Hills Road, Cambridge
CB2 2QQ
Accepted for publication 21 December 1999
AIMS To compare the
clinical and molecular genetic features of two phenotypically distinct
subgroups of families with type 1 Stickler syndrome.
BACKGROUNDStickler
syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and
184840) is a dominantly inherited disorder of collagen connective
tissue, resulting in an abnormal vitreous, myopia, and a variable
degree of orofacial abnormality, deafness, and arthropathy. Stickler
syndrome is the commonest inherited cause of rhegmatogenous retinal
detachment in childhood with a risk of giant retinal tear (GRT) which
is commonly bilateral and a frequent cause of blindness.
METHODPedigrees were
identified from the vitreoretinal service database and subclassified
according to vitreoretinal phenotype. Ophthalmic, skeletal, auditory,
and orofacial features were assessed. Linkage analysis was carried out
with markers for the candidate genes COL2A1, COL11A1, and COL11A2. The
COL2A1 gene was amplified as five overlapping PCR products. Direct
sequencing of individual exons identified mutations.
RESULTSEight families
exhibiting the type 1 vitreous phenotype were studied. Seven were
consistent for linkage to COL2A1, with lod scores ranging from 2.1 to
0.3. In most instances linkage to COL11A1 and COL11A2 could be
excluded. One family was analysed without prior linkage analysis. Three
of the families exhibited a predominantly ocular phenotype with minimal
or absent systemic involvement and were found to have mutations in exon
2 of COL2A1. Five other pedigrees with an identical ocular phenotype
plus orofacial, auditory, and articular involvement had mutations in
others regions of the COL2A1 gene. None of the pedigrees exhibited the
characteristic lenticular, retinal pigment epithelial, or choroidal
changes seen in Wagner syndrome.
CONCLUSIONSThese data
confirm that type 1 Stickler syndrome is caused by mutations in the
gene encoding type II collagen (COL2A1). In addition, data are
submitted showing that mutations involving exon 2 of COL2A1 are
characterised by a predominantly ocular variant of this disorder,
consistent with the major form of type II procollagen in non-ocular
tissues having exon 2 spliced out. Such patients are all at high risk
of retinal detachment. This has important implications for counselling
patients with regard to the development of systemic complications. It
also emphasises the importance and reliability of the ophthalmic
examination in the differential diagnosis of this predominantly ocular
form of Stickler syndrome from Wagner's vitreoretinopathy.
© 2000 by British Journal of Ophthalmology
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