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Investigation of crystallin genes in familial cataract, and report of two disease associated mutations

K P Burdon¹, M G Wirth², D A Mackey³, I M Russell-Eggitt⁴, J E Craig^3,5, J E Elder⁶, J L Dickinson¹ and M M Sale^1,7

¹ Menzies Centre for Population Health Research, University of Tasmania, Hobart, Australia
² Department of Ophthalmology, University of Zürich, Switzerland
³ Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
⁴ Great Ormond Street Hospital for Children, London, UK
⁵ Department of Ophthalmology, Flinders University, Adelaide, Australia
⁶ Department of Ophthalmology, Royal Children’s Hospital, Melbourne, Australia
⁷ Center for Human Genomics and Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, USA

Correspondence to:
Correspondence to:
Dr Michèle M Sale
Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem NC 27157, USA; msale{at}wfubmc.edu

Aims: Mutations of seven crystallin genes have been shown to cause familial cataract. The authors aimed to identify disease causing crystallin mutations in paediatric cataract families from south eastern Australia.

Methods: 38 families with autosomal dominant or recessive paediatric cataract were examined. Three large families were studied by linkage analysis. Candidate genes at regions providing significant LOD scores were sequenced. Single stranded conformational polymorphism (SSCP) analysis was used to screen five crystallin genes in the probands, followed by direct sequencing of observed electrophoretic shifts. Mutations predicted to affect the coding sequence were subsequently investigated in the entire pedigree.

Results: A LOD score of 3.72 was obtained at the -crystallin locus in one pedigree. Sequencing revealed a P23T mutation of CRYGD, found to segregate with disease. A splice site mutation at the first base of intron 3 of the CRYBA1/A3 gene segregating with disease was identified by SSCP in another large family. Five polymorphisms were also detected.

Conclusions: Although mutations in the five crystallin genes comprehensively screened in this study account for 38% of paediatric cataract mutations in the literature, only two causative mutations were detected in 38 pedigrees, suggesting that crystallin mutations are a relatively rare cause of the cataract phenotype in this population.

Keywords: cataract; lens; genetic; crystallin; paediatrics

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