Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease

Abstract

Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected individuals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75); without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 individuals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.

Keywords: DNAJB11; chronic kidney disease; genetics; polycystic kidney disease; prognosis.

Figure 1 |. Distribution of the 17 previously reported and newly described pathogenic variants identified in DNAJB11 (27 pedigrees), and domain organization of DNAJB11.

DNAJB11 is a 358–amino acid protein comprising a highly conserved J domain, with a characteristic His-Pro-Asp (HPD) motif through which it interacts with the chaperone binding immunological protein (BiP), a substrate-binding domain, and a dimerization domain. Although most of the variants identified are loss-of-function variants, the only 2 pathogenic missense variants described occurred in the J domain. ^aNucleotide substitution causing a disruption of the initiation codon. ^bPathogenic variants previously reported by Cornec-Le Gall et al. ^cLast nucleotide of exon 6, the substitution is predicted to weaken the donor site (Berkeley Drosophila Genome Project [BDGP], 0.06 to <0.01; Human Splicing Finder [HSF], 83.39–72.52; and the motif entropy score for the donor site goes from +4.51 to −4.94).

Figure 2 |. Kidney functions and renal survival in DNAJB11-affected individuals.

(a) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) values are plotted against age in 77 patients from 27 families (comprising the 7 previously reported and the 20 newly described pedigrees). Renal function does not differ according to sex. (b) Kaplan-Meier curves show that renal survival does not differ in male and female subjects with a median age at end-stage renal disease (ESRD) of 75 years (0.95 confidence interval, 72.5–77.5 years).

Figure 3 |. Representative abdominal imaging of 15 individuals from 12 families.

(a,e,g,l) Non–contrast-enhanced and (d,m) contrast-enhanced computed tomographies are shown for 6 individuals. (b,c,f,h,i,k,n,o) T2-weighted and (j) T1-weighted magnetic resonance imaging is shown for 10 individuals. Detailed clinical information is available in Table 2.