期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 89, 期 6, 页码 713-730出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2011.11.005
关键词
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资金
- Genome Canada
- National Human Genome Research Institute [HG 005921]
- Michael Smith Foundation for Health Research (MSFHR)
- Austrian Science Foundation (FWF) [P18470]
- Dr.-Legerlotz foundation Austria
- National Institutes of Health (NIH) [R01EY021872]
- Canadian Insitutes of Health Research (CIHR)
- Tiroler Wissenschaftsfonds
- NIH [EY015851, EY03040, 1F31GM079910, R01HD04260, R01DK072301, R01DK075972, KL2RR025015, R01NS064077]
- Gertrud-Kusen-Stiftung
- Science Foundation Ireland President of Ireland [06/Y12/B928]
- Alberta Children's Hospital Foundation
- March of Dimes
- MSFHR
- Sir Jules Thorn Charitable Trust [09/JTA]
- European Community [241955]
- SickKids Foundation/CIHR IHDCYH [NI10-008]
- CIHR Institute of Genetics
- Genome British Columbia
- Canadian Insitutes of Health Research [CIHR]
- Austrian Science Fund (FWF) [P18470] Funding Source: Austrian Science Fund (FWF)
- Medical Research Council [G0700073] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
- MRC [G0700073] Funding Source: UKRI
Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Dania redo (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and cilio-genesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.
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