Mutations in DNAJB13 , Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility - Archive ouverte HAL Access content directly
Journal Articles American Journal of Human Genetics Year : 2016

Mutations in DNAJB13 , Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility

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Patrick Lorès
  • Function : Author
Catherine Faucon
  • Function : Author
Gérard Gacon
  • Function : Author
Aminata Touré
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Abstract

Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ∼15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans.

Dates and versions

inserm-03875562 , version 1 (28-11-2022)

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Cite

Elma El Khouri, Lucie Thomas, Ludovic Jeanson, Emilie Bequignon, Benoit Vallette, et al.. Mutations in DNAJB13 , Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility. American Journal of Human Genetics, 2016, 99 (2), pp.489-500. ⟨10.1016/j.ajhg.2016.06.022⟩. ⟨inserm-03875562⟩
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