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Human Molecular Genetics, 2001, Vol. 10, No. 13 1359-1368
© 2001 Oxford University Press

OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance

Ulrike E.A. Pesch1, Beate Leo-Kottler2, Simone Mayer1, Bernhard Jurklies3, Ulrich Kellner4, Eckart Apfelstedt-Sylla2, Eberhart Zrenner2, Christiane Alexander1,5 and Bernd Wissinger1,+

1Molekulargenetisches Labor der Universitäts-Augenklinik, Auf der Morgenstelle 15, D-72076 Tübingen, Germany, 2Universitäts-Augenklinik, Tübingen, Germany, 3Universitäts-Augenklinik, Essen, Germany, 4Augenklinik, Universitäts-Klinikum Benjamin Franklin, Berlin, Germany and 5Institute of Ophthalmology, Department of Molecular Genetics, University College London, London, UK

We and others have shown recently that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein cause autosomal dominant optic atrophy (ADOA) linked to chromosome 3q28–q29. Here we report screening of the OPA1 gene in a sample of 78 independent ADOA families. OPA1 mutations were identified in 25 patients (detection rate 32.1%) including 16 novel mutations. We successfully amplified OPA1 cDNA prepared from leukocyte RNA of three patients, and found the amount of transcripts harboring the Arg366Stop mutation was significantly reduced compared with transcripts derived from the normal chromosome. Analysis of the distribution of OPA1 mutations in ADOA revealed that most missense mutations cluster within the putative GTPase domain, and that there is a preponderance of mutations, which result in premature translation termination. These observations support the notion that haploinsufficiency may represent a major pathomechanism for ADOA. In addition, we identified an ADOA patient who is a compound heterozygote for two OPA1 missense mutations. The fact that this patient is by far more severely affected than her simple heterozygotic parents and siblings implies that at least these OPA1 alleles behave semi-dominantly rather than purely dominantly. Clinical examination revealed considerable variability in disease expression among patients carrying OPA1 mutations and no strict correlation with either the position or the type of mutation.

+ To whom correspondence should be addressed. Tel: +49 7071 2985032; Fax: +49 7071 295725; Email: wissinger@uni-tuebingen.de


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