Francis, Peter James; (2001) Clinical and genetic heterogeneity of human cataract. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Human inherited congenital cataract is phenotypically heterogeneous most likely reflecting a complex underlying genotype. The visual prognosis for childhood cataract of all aetiologies is poor. There is however very limited information about the outcome of patients with isolated congenital cataract. Aims: (1) to establish the phenotypic variability of human inherited cataract (HIC). (2) to determine the visual outcome and surgical complications. (3) to identify and characterise novel genes implicated in cataract. Methods: HIC families were identified from hospital databases. All individuals provided a history and underwent an ocular examination. Linkage analysis, mutation detection and functional analysis of mutations identified were undertaken using appropriate expression systems. Results: (1) 586 individuals (284 affected) from 76 pedigrees participated. Cataract phenotypes could be categorised as one of ten distinct phenotypes. (2) The visual outcome and surgical complication rate was found to be significantly better in our group of isolated cataracts when compared to congenital cataracts of all aetiologies. (3) Novel cataract loci were identified on (a) 12q and different missense mutations in the MIP gene identified in two families. Functional analysis showed that the mutants abolish the water channel function of the protein, (b) 2q. Candidate gene screening of the 2q locus did not reveal a mutation within the y-crystallin gene cluster, (c) Xp. (d) lip. (e) l0q. (f) 11q. (4) Linkage to known cataract loci was excluded in two other families. Conclusions: This study has enabled categorisation of HIC into ten phenotypes. It has shown that patients have better visual and surgical outcomes than those with cataracts of other aetiologies probably due to the lack of attendant developmental abnormalities and because surgery may often be delayed. Four novel cataract loci have been identified. The recognition of mutations in MIP confirms the importance of this protein in both normal lens physiology and cataractogenesis. Furthermore, the functional analyses provide a molecular basis for the cataracts observed.

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