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

Details

Serval ID
serval:BIB_9C74FB2128F9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
Journal
American journal of human genetics
Author(s)
El Khouri E., Thomas L., Jeanson L., Bequignon E., Vallette B., Duquesnoy P., Montantin G., Copin B., Dastot-Le Moal F., Blanchon S., Papon J.F., Lorès P., Yuan L., Collot N., Tissier S., Faucon C., Gacon G., Patrat C., Wolf J.P., Dulioust E., Crestani B., Escudier E., Coste A., Legendre M., Touré A., Amselem S.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
04/08/2016
Peer-reviewed
Oui
Volume
99
Number
2
Pages
489-500
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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.
Keywords
Adolescent, Axoneme/genetics, Cilia/genetics, Ciliary Motility Disorders/genetics, Ciliary Motility Disorders/pathology, Exome/genetics, Female, Flagella/genetics, Flagella/pathology, HSP40 Heat-Shock Proteins/metabolism, Heat-Shock Proteins/genetics, Heat-Shock Proteins/metabolism, Homozygote, Humans, Infertility, Male/genetics, Infertility, Male/pathology, Kartagener Syndrome/genetics, Male, Middle Aged, Mutation, Mutation, Missense/genetics, Phenotype, Polymorphism, Single Nucleotide/genetics, Proteasome Endopeptidase Complex/metabolism, Protein Stability, RNA Splicing/genetics, Semen, Spermatozoa/metabolism, Spermatozoa/pathology, DNAJB13, PCD, central complex, cilia, radial spoke, sperm flagellum
Pubmed
Web of science
Open Access
Yes
Create date
15/05/2020 16:27
Last modification date
16/05/2020 5:26
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