Ghent University Academic Bibliography

Advanced

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

Riza Köksal Özgül, Anna M Siemiatkowska, Didem Yücel, Connie A Myers, Rob WJ Collin, Marijke N Zonneveld, Avigail Beryozkin, Eyal Banin, Carel B Hoyng and L Ingeborgh van den Born, et al. (2011) AMERICAN JOURNAL OF HUMAN GENETICS. 89(2). p.253-264
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 (MA K) 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
RHODOPSIN GENE, KINASE, RETINAL DISEASE, FLAGELLAR LENGTH, TRANSCRIPTIONAL NETWORK, GENOME BROWSER DATABASE, CHIP-SEQ REVEALS, MOUSE, FAMILY, CRX
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
89
issue
2
pages
253 - 264
Web of Science type
Article
Web of Science id
000294148800005
JCR category
GENETICS & HEREDITY
JCR impact factor
10.603 (2011)
JCR rank
8/155 (2011)
JCR quartile
1 (2011)
ISSN
0002-9297
DOI
10.1016/j.ajhg.2011.07.005
language
English
UGent publication?
no
classification
A1
additional info
Dr. Elfride De Baere and Dr. Bart Leroy are members of the European Retinal Disease Consortium
copyright statement
I have transferred the copyright for this publication to the publisher
id
2054628
handle
http://hdl.handle.net/1854/LU-2054628
date created
2012-03-01 10:42:56
date last changed
2012-04-13 09:57:24
@article{2054628,
  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 (MA K) 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.},
  author       = {{\"O}zg{\"u}l, Riza K{\"o}ksal and Siemiatkowska, Anna M and Y{\"u}cel, Didem and Myers, Connie A and Collin, Rob WJ and Zonneveld, Marijke N and Beryozkin, Avigail and Banin, Eyal and Hoyng, Carel B and van den Born, L Ingeborgh and European Retinal Disease Consortium, the and Bose, Ron and Shen, Wei and Sharon, Dror and Cremers, Frans PM and Klevering, B Jeroen and den Hollander, Anneke I and Corbo, Joseph C and De Baere, Elfride and Leroy, Bart},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {RHODOPSIN GENE,KINASE,RETINAL DISEASE,FLAGELLAR LENGTH,TRANSCRIPTIONAL NETWORK,GENOME BROWSER DATABASE,CHIP-SEQ REVEALS,MOUSE,FAMILY,CRX},
  language     = {eng},
  number       = {2},
  pages        = {253--264},
  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},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2011.07.005},
  volume       = {89},
  year         = {2011},
}

Chicago
Özgül, Riza Köksal, Anna M Siemiatkowska, Didem Yücel, Connie A Myers, Rob WJ Collin, Marijke N Zonneveld, Avigail Beryozkin, et al. 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.” American Journal of Human Genetics 89 (2): 253–264.
APA
Özgül, R. K., Siemiatkowska, A. M., Yücel, D., Myers, C. A., Collin, R. W., Zonneveld, M. N., Beryozkin, A., et al. (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. AMERICAN JOURNAL OF HUMAN GENETICS, 89(2), 253–264.
Vancouver
1.
Özgül RK, Siemiatkowska AM, Yücel D, Myers CA, Collin RW, Zonneveld MN, et al. Exome sequencing and cis-regulatory mapping identify mutations in MAK, a gene encoding a regulator of ciliary length, as a cause of retinitis pigmentosa. AMERICAN JOURNAL OF HUMAN GENETICS. 2011;89(2):253–64.
MLA
Özgül, Riza Köksal, Anna M Siemiatkowska, Didem Yücel, et al. “Exome Sequencing and Cis-regulatory Mapping Identify Mutations in MAK, a Gene Encoding a Regulator of Ciliary Length, as a Cause of Retinitis Pigmentosa.” AMERICAN JOURNAL OF HUMAN GENETICS 89.2 (2011): 253–264. Print.