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.

Highlights

  • Jeune asphyxiating thoracic dystrophy (JATD [MIM208500]) is a very rare skeletal dysplasia affecting 1:100 000 live births [1]

  • In order to test whether the variant we identified in centrosomal protein of 120 kD (CEP120) is disease-causing, we sought to search for likely pathogenic variants in this gene in independent individuals

  • Most of the genes implicated in the pathogenesis of JATD are involved in intraflagellar transport (IFT), but there are precedents for genes encoding resident centriolar proteins being mutated in skeletal ciliopathies and in JATD

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Summary

Introduction

Jeune asphyxiating thoracic dystrophy (JATD [MIM208500]) is a very rare skeletal dysplasia affecting 1:100 000 live births [1]. JATD individuals can have a cerebellar hypoplasia pattern typical of Joubert syndrome [5], abnormal retina typical of cilia-related retinal dystrophy [6] and cystic renal changes typical of nephronophthisis [7,8]. These clinical observations have been corroborated over the past few years by the demonstration that JATD can be caused by mutations in genes that encode various ciliary proteins, which justifies the classification of JATD as a skeletal ciliopathy [2]

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