期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 5, 页码 1410-1419出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu555
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资金
- DHFMR
- Wellcome Trust [WT091310]
- Action Medical Research UK Clinical Training Fellowship [RTF-1411]
- Radboud Excellence Fellowship
- Radboud UMC Hypatia Fellowship
- Dutch Kidney Foundation [CP11.18]
- European Community [241955]
- Great Ormond Street Hospital Children's Charity
- German Ministry for Education and Research (BMBF, FACE consortium) [01GM1109A, TP1]
- European Commission (SYBIL consortium) [602300, A27]
- Milena Carvajal Pro-Kartagener Foundation
- Action Medical Research [GN2101]
- Newlife Foundation for Disabled Children UK [10-11/15]
- Association Francaise Contre les Myopathies
- Wellcome Trust
- Action Medical Research [2101, 1794] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299, V1296] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10008, NF-SI-0510-10268] Funding Source: researchfish
Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies.
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