Submission Details

DNAJB13, a gene encoding a heat shock protein (HSP40) co-chaperone, was first reported in relation to Primary Ciliary Dyskinesia by El Khouri E, et al., 2016, PMID: 27486783. These authors comment that although its activity as a possible HSP co-chaperone cannot be excluded, it lacks a relevant HSP stimulating protein motif and they conclude that it might function solely as a structural component of the radial spoke (based on work on its Chlamydomonas orthologue).

Four variants that have been reported in four patients in two publications (PMIDs: 27486783 and 35166991) and in ClinVar SCV002768109.2 (VCV001805029.2) are included in this curation. The probands’ phenotypes include recurrent respiratory tract infections, reduced nasal nitric oxide, and male infertility without situs inversus. The mechanism of pathogenicity appears to be loss of function. Transmission electron microscopy (TEM) analysis of the respiratory cilia obtained by nasal biopsy from two patients in PMID: 27486783 showed an abnormal percentage of cilia lacking central microtubule(s), including mainly cilia with a “9 + 0” pattern and some rare cilia with a “9 + 1” or a “8 + 1” pattern. Immunofluorescence studies showed DNAJB13 protein to be absent from airway cilia and sperm flagella of one male patient (DCP813). Cilia movement analysis by HSVM showed a reduced CBF and reduced beat amplitude in the probands (siblings DCP812 and DCP813 both carrying c.833T>G -p.Met278Arg) but normal cilia movement in the proband DCP856 carrying c.68+1G>C -p.Tyr24*) variant. This suggests functional cilia impairment may be only caused by c.833T>G -p.(Met278Arg) variant, but not by c.68+1G>C -p.(Tyr24*) variant; ciliary TEM was inconclusive for the p.(Tyr24*) case. For the single case in PMID: 35166991 which carried homozygous c.335_336del (p.Glu112Valfs*3) variants, no airway cilia were examined but the sperm had a disrupted axonemal structure including absent central microtubules. In this case, possible PCD signs included chronic coughing and recurrent respiratory infections with “increased and disordered lung texture” in CT scan.

This gene-disease relationship is also supported by experimental evidence. Expression studies show that DNAJB13 is differentially expressed in PCD relevant tissues. qRT-PCR analysis on a tissue panel revealed that DNAJB13 is mainly expressed in the trachea and testis. High amounts of transcripts were detected in airway epithelial cells (AECs) obtained by nasal biopsy of healthy individuals. Immunofluorescence microscopy revealed that DNAJB13 co-localizes with α-tubulin along the length of cilia and flagella (PMID: 27486783). TEM analysis of the sperm from a primary infertile patient carrying biallelic DNAJB13 variants revealed aberrant heads as well as anomalies of the flagella (PMID: 35166991). Fluorescent images of spermatozoa collected from chimeric mice with Dnajb13 KO ESCs showed immotile tailless and short-tailed spermatozoa. No abnormalities were detected in the cilia of the lateral ventricle of Dnajb13 KO mice (PMID: 27530713).

In summary, there is moderate evidence supporting the relationship between DNAJB13 and autosomal recessive Primary Ciliary Dyskinesia. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.