DNAJB11 – Atypical Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (MONDO:0004691) is most frequently caused by PKD1 and PKD2 variants, but a subset of families harbors pathogenic variants in non-canonical genes. DNAJB11, encoding the ER co-chaperone ERdj3, has been implicated as a minor locus in ADPKD, presenting with an attenuated cystic phenotype and variable extrarenal features.

In a multicenter study of atypical ADPKD cohorts, truncating variants in DNAJB11 were identified in 27 patients across 6 families sharing the recurrent c.100C>T (p.Arg34Ter) variant (PMID:35664268). An international collaboration further reported 13 distinct loss-of-function variants in DNAJB11 among 77 affected individuals from 27 pedigrees (PMID:32631624). These variants include canonical splice-site changes (e.g., c.456+2T>A), frameshifts (e.g., c.781_782del (p.Asn261fs)), and nonsense mutations such as c.100C>T (p.Arg34Ter).

DNAJB11-related ADPKD follows an autosomal dominant inheritance pattern, with segregation of pathogenic variants in 27 independent families (PMID:32631624). Affected relatives totaled 77 across these pedigrees, demonstrating co-segregation of heterozygous loss-of-function alleles and disease.

Phenotypically, DNAJB11-PKD patients exhibit small or normal-sized kidneys with fewer and smaller cysts, slower decline in renal function, and later onset of end-stage kidney disease compared with PKD1/PKD2 cases. Proteinuria and nephrolithiasis are common (PMID:35664268), and cohorts show increased prevalence of type 2 diabetes mellitus and hyperuricemia (PMID:38275584).

Functional studies of ERdj3 demonstrate that loss of its J-domain activity impairs release from unfolded substrates and ER-associated degradation, supporting a haploinsufficiency mechanism in vivo (PMID:15525676; PMID:25143379). Disruption of ER protein quality control likely contributes to cystogenesis and interstitial fibrosis in renal tubular cells.

Together, robust genetic segregation in 27 pedigrees and concordant biochemical evidence establish a Strong clinical validity for DNAJB11 in ADPKD. Additional functional data reinforce a Moderate tier for experimental evidence under a haploinsufficiency model. Clinically, identification of DNAJB11 mutations guides prognosis and management in patients with atypical ADPKD phenotypes.

References

• Kidney international • 2020 • Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease PMID:32631624
• European journal of human genetics • 2022 • Atypical ADPKD due to DNAJB11 truncating variants in six families PMID:35664268
• Genes • 2023 • DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort PMID:38275584
• Molecular biology of the cell • 2005 • ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates PMID:15525676
• The Journal of biological chemistry • 2014 • Dissection of structural and functional requirements that underlie the interaction of ERdj3 protein with substrates in the endoplasmic reticulum PMID:25143379

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