A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies

Hum Mol Genet. 2015 Mar 1;24(5):1410-9. doi: 10.1093/hmg/ddu555.

Ranad Shaheen ¹, Miriam Schmidts ², Eissa Faqeih ³, Amal Hashem ⁴, Ekkehart Lausch ⁵, Isabel Holder ⁶, Andrea Superti-Furga ⁷, UK10K Consortium, Hannah M Mitchison ⁶, Agaadir Almoisheer ¹, Rana Alamro ¹, Tarfa Alshiddi ¹, Fatma Alzahrani ¹, Philip L Beales ⁸, Fowzan S Alkuraya ⁹

Affiliations

1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
2 Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, the Netherlands.
3 Department of Pediatrics, King Fahad Medical City, Riyadh 59046, Saudi Arabia.
4 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
5 Pediatric Genetics Division, Center for Adolescent and Pediatric Medicine, University Hospital Freiburg, Freiburg 79108, Germany.
6 Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
7 Department of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne 1011, Switzerland.
8 Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, falkuraya@kfshrc.edu.sa p.beales@ucl.ac.uk.
9 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia, Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia falkuraya@kfshrc.edu.sa p.beales@ucl.ac.uk.

PMID: 25361962 DOI: 10.1093/hmg/ddu555

Abstract

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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