Fuchs endothelial corneal dystrophy (FECD) MIM#136800 and posterior polymorphous corneal dystrophy (PPCD) MIM#122000 both belong to the corneal endothelial dystrophies in which endothelial dysfunction can lead to corneal oedema. In addition, they both share the common features of endothelial metaplasia and the secretion of an abnormal Descemet's membrane as a pathological posterior collagenous layer (PCL) with a small or absent posterior non‐banded zone.1,2
The exact cause of both FECD and PPCD is still unknown, although both are thought to be the result of a disorder of neural crest terminal differentiation.3 Mutations in COL8A2, the gene for the α2(VIII) chain of type VIII collagen, have previously been described in patients with both FECD and PPCD,4,5 and type VIII collagen is found in both normal anterior banded Descemet's membrane and in the PCL of patients with both FECD and PPCD.6 In vivo type VIII collagen may exist as homotrimers or heterotrimers of both α2(VIII) and α1(VIII) chains.7,8 Therefore COL8A1, the gene for the α1(VIII) chain of type VIII collagen, was an ideal candidate for both FECD and PPCD.
DNA was made available for analysis from 141 unrelated patients with either FECD (n = 124) or PPCD (n = 17). Data for age of onset were available from 102 (72%) patients with FECD and gave a mean age of onset of 63 (standard deviation (SD) 11) years. Mutation screening of the coding region and part of the surrounding non‐coding region of COL8A1 was carried out for all patients and identified two sequence variations in two different patients with FECD (fig 1; table 1). Both are presumed to be non‐pathogenic as neither are likely to alter splicing nor alter the amino acid sequence for the α1(VIII) chain of type VIII collagen.
Figure 1 Sequence variations in two patients with Fuchs endothelial corneal dystrophy.
Table 1 Sequence variations in COL8A1.
| Diagnosis | Sequence change | Amino acid change | Description |
|---|---|---|---|
| FECD | 1860C>T | A620A | Silent polymorphism |
| FECD | 2240delT | – | After the end of coding sequence |
Changes numbered according to Genbank accession number NM_001850.
FECD, Fuchs endothelial corneal dystrophy.
These results suggest that COL8A1 is unlikely to be implicated in the aetiology of either FECD or PPCD, although the possibility of pathogenic changes within the promoter region of COL8A1 cannot be excluded at this time.
In a study of 116 patients with FECD, possible pathogenic mutations were found in 9 (8%) patients and in only one family with PPCD.4 This suggests the presence of genetic heterogeneity, and therefore possible pathogenic mutations may not have been found in the present study as not enough patients were examined. This, however, seems unlikely as both studies used a similar number of patients.
These results also support the hypothesis that type VIII collagen exists in vivo as homotrimers of either α1(VIII) or α2(VIII) and not as heterotrimers. In vitro translation studies supplemented with semi‐permeabilised cells have shown that it is possible for type VIII collagen to consist of heterotrimers.8 Conversely, immunolocalisation studies by Greenhill et al7 using chain‐specific antibodies showed different localisation patterns for the two type VIII collagen chains in the human cornea. This, coupled with the results of the present study, suggests that type VIII collagen exists as homotrimers within the cornea and that each performs a different function.
In conclusion, we have excluded the COL8A1 gene as a candidate for both FECD and PPCD. Analysis of FECD families not showing linkage to the COL8A2 locus will enable the identification of other candidate genes.4 In addition, genes associated with the pathogenesis of PPCD remain to be identified within the PPCD1 and PPCD3 loci on chromosome 20 and chromosome 10, respectively.9,10
Acknowledgements
GCMB is a Wellcome Trust Senior Clinical Research Fellow. Ethical approval (REC 05/Q1407/164) has been granted for this work. The authors have no competing interests in the completion of this work.
Footnotes
Competing interests: None.
References
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