TY - JOUR
T1 - Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa
AU - Özgül, Rza Köksal
AU - Siemiatkowska, Anna M.
AU - Yücel, Didem
AU - Myers, Connie A.
AU - Collin, Rob W.J.
AU - Zonneveld, Marijke N.
AU - Beryozkin, Avigail
AU - Banin, Eyal
AU - Hoyng, Carel B.
AU - Van Den Born, L. Ingeborgh
AU - Bose, Ron
AU - Shen, Wei
AU - Sharon, Dror
AU - Cremers, Frans P.M.
AU - Klevering, B. Jeroen
AU - Den Hollander, Anneke I.
AU - Corbo, Joseph C.
N1 - Funding Information:
We sincerely thank all of the families that participated in this study. We also would like to thank Bill Harbour, Mohammed Hussaini, Serkan Kaygın, Lütfiye Mesci, and Atilla Göknur. The European Retinal Disease Consortium consists of Carmen Ayuso, Sandro Banfi, Tamar Ben-Yosef, Elfride de Baere, Christian Hamel, Chris Inglehearn, Robert K. Koenekoop, Susanne Kohl, Bart P. Leroy, Carmel Toomes, and Bernd Wissinger. This work was supported by the National Eye Institute (EY018826), the Hope Center for Neurologic Diseases, and the American Health Assistance Foundation to J.C.C.; the Netherlands Organisation for Scientific Research (TOP-grant 40-00812-98-09047) to F.P.M.C. and A.I.d.H.; the Foundation Fighting Blindness USA (grant BR-GE-0510-04890RAD) to A.I.d.H.; the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, the Gelderse Blinden Stichting, the Landelijke Stichting voor Blinden en Slechtzienden, Retina Nederland, the Stichting Oogfonds Nederland, and the Rotterdamse Vereniging Blindenbelangen to F.P.M.C.; and Hacettepe University Research Fund (801601003) to R.K.Ö. and a grant from the Foundation Fighting Blindness (BR-GE-0510-0490-HUJ) to D.S.
PY - 2011/8/12
Y1 - 2011/8/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80051608305&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2011.07.005
DO - 10.1016/j.ajhg.2011.07.005
M3 - Article
C2 - 21835304
AN - SCOPUS:80051608305
SN - 0002-9297
VL - 89
SP - 253
EP - 264
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -