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

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.

SUBMITTER: El Khouri E

PROVIDER: S-EPMC4974111 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

El Khouri Elma E Thomas Lucie L Jeanson Ludovic L Bequignon Emilie E Vallette Benoit B Duquesnoy Philippe P Montantin Guy G Copin Bruno B Dastot-Le Moal Florence F Blanchon Sylvain S Papon Jean François JF Lorès Patrick P Yuan Li L Collot Nathalie N Tissier Sylvie S Faucon Catherine C Gacon Gérard G Patrat Catherine C Wolf Jean Philippe JP Dulioust Emmanuel E Crestani Bruno B Escudier Estelle E Coste André A Legendre Marie M Touré Aminata A Amselem Serge S

American journal of human genetics 20160801 2

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 ...[more]

PMID: 27486783

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Project description:Trial designPrimary ciliary dyskinesia (PCD) is a genetical disease that inherited in an autosomal-recessive way. Its clinical manifestations (such as male infertility) are mainly caused by defects of motion-related cilia that encoded by mutated genes. Although some mutation has been verified, a number of mutations of PCD remain elusive. The main purpose of this study is to identify mutant genes in a Chinese family with PCD, and to verify the safety and effectiveness of intracytoplasmic sperm injection (ICSI) of infertility caused by PCD.MethodsImaging examination was used to exclude pulmonary inflammation and visceral translocation. Semen analysis was used to assess the quality of the proband's sperm. Transmission electron microscopy (TEM) was conducted to assess the ultrastructure of flagella and cilia. Targeted next generation sequencing and Sanger sequencing and qPCR (real-time quantitative polymerase chain reaction detecting system) were applied to identified mutation of Chinese Family suspected of having PCD. Viable sperm were selected by hypo-osmotic swelling test (HOST) for ICSI.ResultsWe report 2 novel mutations in CCDC40 gene (c.1259delA and EX17_20 deletion) resulted in immobility of sperm and infertility of the proband. These mutations were confirmed in the proband's sister (heterozygous) and his parents (recessive carrier) by Sanger sequencing and qPCR. All the spermatozoa from the proband were immotile. Ultrastructural defects were found in flagella and cilia of proband and his sister. Viable sperms were selected by HOST for ICSI and fertilized 9 of 21 eggs. Two frozen embryos were transplanted and a healthy 3500 g boy was delivered at 40 + 4 weeks' gestation. And then, we summarized the genes related to PCD and the mutant sites of CCDC40 gene.ConclusionWe reported 2 novel mutants in CCDC40 gene (c.1259delA and EX17_20 deletion), which could be candidates for genetic diagnosis in PCD patients. The combination of targeted next generation sequencing and Sanger sequencing may be a useful tool to diagnose PCD. ICSI is a considerable method in treatment of infertility caused by PCD.

Dataset Information

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

Publications

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

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