Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa

Rıza Köksal Ozgül, Anna M Siemiatkowska, Didem Yücel, Connie A Myers, Rob W J Collin, Marijke N Zonneveld, Avigail Beryozkin, Eyal Banin, Carel B Hoyng, L Ingeborgh van den Born, , Ron Bose, Wei Shen, Dror Sharon, Frans P M Cremers, B Jeroen Klevering, Anneke I den Hollander, Joseph C Corbo

Research output: Contribution to journalArticleResearchpeer-review


A fundamental challenge in analyzing exome-sequence data is distinguishing pathogenic mutations from background polymorphisms. To address this problem in the context of a genetically heterogeneous disease, retinitis pigmentosa (RP), we devised a candidate-gene prioritization strategy called cis-regulatory mapping that utilizes ChIP-seq data for the photoreceptor transcription factor CRX to rank candidate genes. Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with RP. MAK encodes a cilium-associated mitogen-activated protein kinase whose function is conserved from the ciliated alga, Chlamydomonas reinhardtii, to humans. Mutations in MAK orthologs in mice and other model organisms result in abnormally long cilia and, in mice, rapid photoreceptor degeneration. Subsequent sequence analyses of additional individuals with RP identified five probands with missense mutations in MAK. Two of these mutations alter amino acids that are conserved in all known kinases, and an in vitro kinase assay indicates that these mutations result in a loss of kinase activity. Thus, kinase activity appears to be critical for MAK function in humans. This study highlights a previously underappreciated role for CRX as a direct transcriptional regulator of ciliary genes in photoreceptors. In addition, it 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.

Original languageEnglish
Pages (from-to)253-64
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 12 Aug 2011


  • Adult
  • Amino Acid Sequence
  • Animals
  • Chromosome Mapping
  • Cilia/enzymology
  • Exons/genetics
  • Female
  • Genes, Recessive/genetics
  • Genetic Loci/genetics
  • Homeodomain Proteins/metabolism
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Mutation/genetics
  • Pedigree
  • Photoreceptor Cells, Vertebrate/metabolism
  • Protein-Serine-Threonine Kinases/chemistry
  • Regulatory Sequences, Nucleic Acid/genetics
  • Retinitis Pigmentosa/enzymology
  • Rhodopsin/genetics
  • Sequence Analysis, DNA
  • Trans-Activators/metabolism
  • Transcription, Genetic
  • Young Adult


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