Cis-regulatory mapping combined with exome sequencing identifies a gene involved in inherited blindness

Ozgul figure

A group of researchers at the Departments of Ophthalmology and Human Genetics have recently published an article in the American Journal of Human Genetics using cis-regulatory mapping combined with exome sequencing to identify mutations in MAK, a gene encoding Male-Associated Kinase, as a cause of autosomal recessive retinitis pigmentosa. The study was performed in close collaboration with Dr. Joseph Corbo at Washington University in St. Louis.

Exome sequencing is an efficient strategy to selectively sequence the coding regions of the human genome to identify novel genes associated with human disease. A fundamental challenge in analyzing exome sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem the researchers devised a candidate gene prioritization strategy called 'cis-regulatory mapping' which utilizes ChIP-seq data for the photoreceptor-specific transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in MAK in the single affected member of a consanguineous Turkish family with retinitis pigmentosa.

MAK encodes a cilium-associated MAP kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK homologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional patients with retinitis pigmentosa identified five patients with missense mutations in MAK. Two of these mutations alter amino acids which are conserved in all known kinases, and an in vitro kinase assay indicated that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study demonstrates the effectiveness of CRX-based cis-regulatory mapping in prioritizing candidate genes from exome data, and suggests that this strategy should be generally applicable to a range of retinal diseases.

Ozgul RK*, Siemiatkowska AM*, Yucel D*, Myers CA, Collin RWJ, Zonneveld MN, Beryozkin A, Banin E, Hoyng CB, van den Born LI, the European Retinal Disease Consortium, Bose R, Shen W, Sharon D, Cremers FPM, Klevering BJ, den Hollander AI**, Corbo JC** (2011). Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa. Am J Hum Genet 89:253-264. *shared first authors; **corresponding authors

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