title: Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa.
abstract: 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.
authors.affiliation: Institute of Child Health and Metabolism Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Rıza Köksal
authors.initials: RK
authors.lastname: Ozgül
authors.forename: Anna M
authors.initials: AM
authors.lastname: Siemiatkowska
authors.forename: Didem
authors.initials: D
authors.lastname: Yücel
authors.forename: Connie A
authors.initials: CA
authors.lastname: Myers
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Zonneveld
authors.forename: Avigail
authors.initials: A
authors.lastname: Beryozkin
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Ron
authors.initials: R
authors.lastname: Bose
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: B Jeroen
authors.initials: BJ
authors.lastname: Klevering
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Corbo
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002923:Cilia / Q000201:enzymology / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein; D012243:Rhodopsin; D017346:Protein Serine-Threonine Kinases; C081931:MAK protein, human