Human Molecular Genetics, 2001, Vol. 10, No. 13 1369-1378
© 2001 Oxford University Press
Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy
Molecular Medicine Unit, Clinical Sciences Building, University of Leeds, St James’s University Hospital, Leeds, LS9 7TF, UK, 1CERA, Victorian Eye and Ear Hospital, Melbourne, Australia, 2Department of Clinical Genetics, St Michael’s Hospital, Southwell Street, Bristol, UK, 3Department of Clinical Genetics, Ashley Wing, St James’s University Hospital, Leeds, UK, 4Doncaster Royal Infirmary, Thorne Road, Doncaster, UK, 5Manchester Royal Eye Hospital/Department of Clinical Genetics, Oxford Road, Manchester, UK and 6West Sussex Eye Unit, Worthing and St Richards’s Hospital, Worthing, UK
Dominant optic atrophy (DOA) is the commonest form of inherited optic neuropathy. Although heterogeneous, a major locus has been mapped to chromosome 3q28 and the gene responsible, OPA1, was recently identified. We therefore screened a panel of 35 DOA patients for mutations in OPA1. This revealed 14 novel mutations and a further three known mutations, which together accounted for 20 of the 35 families (57%) included in this study. This more than doubles the number of OPA1 mutations reported in the literature, bringing the total to 25. These are predominantly null mutations generating truncated proteins, strongly suggesting that the mechanism underlying DOA is haploinsufficiency. The mutations are largely family-specific, although a common 4 bp deletion in exon 27 (eight different families) and missense mutations in exons 8 (two families) and 9 (two families) have been identified. Haplotype analysis of individuals with the exon 27 2708del(TTAG) mutation suggests that this is a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. The mutation screening in this study also identified a number of asymptomatic individuals with OPA1 mutations. A re-calculation of the penetrance of this disorder within two of our families indicates figures as low as 43 and 62% associated with the 2708del(TTAG) mutation. If haploinsufficiency is the mechanism underlying DOA it is unlikely that this figure will be mutation-specific, indicating that the penetrance in DOA is much lower than the 98% reported previously. To investigate whether Leber’s hereditary optic neuropathy (LHON) could be caused by mutations in OPA1 we also screened a panel of 28 LHON patients who tested negatively for the three major LHON mutations. No mutations were identified in any LHON patients, indicating that DOA and LHON are genetically distinct.
+ To whom correspondence should be addressed. Tel: +44 113 206 5698; Fax: +44 113 244 4475; Email: cinglehe@hgmp.mrc.ac.ukThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First AuthorsPresent address: Amanda J. Churchill, Bristol Eye Hospital, Lower Maudlin Street, Bristol, UK
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