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D. F. Schorderet, B. Polok, P. Escher, T. Favez, N. Voirol, S. Bolay, A. Ambresin, C. Hamel, A. Mégarbané, F. L. Munier; The Metal Ion Binding Protein Cnnm4 Is Mutated in the Rod-Cone Dystrophy/Amelogenesis Imperfecta Syndrome. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2324.
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To identify the gene causing rod-cone dystrophy/amelogenesis imperfecta
Homozygosity mapping was performed using the Affymetrix 50K XbaI array in one family and candidate genes in the linked interval were sequenced with ABI Dye Terminator, vers. 1 in the index patient of 3 families. The identified mutations were screened in normal control individuals. Expression analyses were performed on RNA extracted from the brain, various parts of the eye and teeth; immunostaining was done on mouse eyes and jaw and knock-down experiments were carried out in zebrafish embroys.
Sequencing the coding regions of ancient conserved domain protein 4 (CNNM4), a metal ions transporter, revealed a 1-base pair duplication (p.L438fs) in family A, a p.R236Q mutation in family B and a p.L324P in family C. All these mutations were homozygous and involved very conserved amino acids in paralogs and orthologs. Immunostaining and RT-PCR confirmed that CNNM4 was strongly expressed in various parts of the eye and in the teeth. Morpholino experiments in zebrafish showed a loss of ganglion cells at 5 days post fertilization.
The rod-cone dystrophy/amelogenesis imperfecta syndrome is caused by mutation in CNNM4 and is due to aberrant metal ion homeostasis.
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