Mutation spectra in PITPNM3 known as a cause of autosomal dominant cone rod dystrophy (CORD5). L. Kohn1, S. Haraldsson1, S. Kohl2, C. F. Inglehearn3, O. Sandgren4, I. Golovleva1 1) Medical Biosciences/Medical and Clinical Genetics, Umeå University, Sweden; 2) Centre for Ophthalmology, Institute for Ophthalmic Research, Molecular Genetics Laboratory, Tübingen, Germany; 3) Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, St. Jamess University Hospital, Leeds, United Kingdom; 4) Clinical Biosciences/Ophthalmology, Umeå University, Sweden.
Autosomal dominant cone dystrophy (CORD5) is a rare disease predominantly affecting the cone photoreceptor cells. The main clinical symptoms are impaired visual acuity, sensitivity for light and defective colour vision. The disease locus was initially mapped to chromosome 17p13 and later on narrowed down from 27 cM to 14.3 cM exploring material from two Swedish families (Balciuniene et al, 1995; Köhn et al, 2007). Sequencing of a candidate gene, phosphatidylinositol transfer membrane-associated protein (PITPNM3) revealed a missense mutation, Q626H. PITPNM3 known as a human homolog of the Drosophila retinal degeneration B (rdgB) gene is needed for transport of phospholipids, renewal of photoreceptors membrane and provides the ERG response to light. The plausible mutation causing CORD5 is located in the C-terminal region interacting with a member of nonreceptor protein tyrosine kinases, PYK2. Through collaboration with research groups in Germany and UK we have ascertained DNA from cone and cone-rod dystrophy patients for further screening of PITPNM3 to establish the global impact of this gene in retinal diseases. Mutation screening of PITPNM3 was performed by dHPLC (WAVE, Transgenomic) followed by DNA-sequencing. 111 samples were analysed in total. Several potential pathogenic mutations located in both coding and intronic sequences were found in the trial. Matched control populations are currently screened to elucidate whether or not these sequence variations are true mutations. In conclusion, the findings of additional mutations to Q626H in PITPNM3 will provide stronger evidence for novel pathways and a potential important role of PITPNM3 in mammalian phototransduction and molecular pathogenesis of retinal degenerations.