AD structural kidney disorders

DNAJB11 is a recently reported mutation associated to a cystic phenotype that still requires to be described in a wider number of patients due to its rarity and its relatively novelty.
DNAJB11 was observed to play a central role in the maintenance of the endoplasmic reticulum (ER) protein homeostasis, as it encodes for the glycoprotein ERdj3, which acts as a binding immunoglobulin protein (BiP) co-chaperone. BiP (also known as GRP78) is a heat shock protein chaperone required for the proper folding and assembly of proteins in the ER [1]. It targets misfolded proteins to ER degradation and acts as a master regulator of the unfolded protein response, an adaptive cellular response to ER stress [2]. In the presence of an altered mechanism, the loss of maturation and appropriate localization of polycystin-1 (encoded by PKD1) are the main observed results that are linked to the initiation and enlargement of kidney and liver cysts [3,4]. A DNAJB11 pathogenic variant was also observed, in the literature, to be related with the retention of uromodulin in tubular ascending loop of Henle (TAL) cells, mimicking ADTKD-UMOD cellular phenotypes [5].

In terms of clinical presentation, these pathophysiological mechanisms are expressed with kidney cysts, hyperuricemia, episodes of nephrolithiasis and Type 2 Diabetes Mellitus [2,5,6]. This is the main reason for which Cornec-Le Gall et al. [5] firstly postulated that a pathogenic variant in DNAJB11 leads to a disease partially overlapping between ADPKD and ADTKD. This is, in our opinion, the main peculiarity of this mutation that should be further investigated in a broader cohort of affected individuals. The kidneys, as previously stated, present with bilateral cysts that, however, do not result in the distinctive enlargement of typical ADPKD patients, but in normal-size kidneys. Indeed, bilateral small cysts were the most common finding both in the literature, and in our cohort, when we assessed it for this type of mutation [7]. On the contrary, hepatic cysts are frequently less found in individuals with this mutation, while nephrolithiasis was diagnosed in an important number of patients. Moreover, these subjects normally reach ESRD at an older age, when compared to patients carrying a PKD1/PKD2 pathogenic variant.

With regards to the histological data, we recently performed a kidney biopsy on an affected individual. It showed a disproportionate presence between interstitial fibrosis and tubular atrophy, with a prevalence of interstitial fibrosis that could be observed in ~60% of the sample, and the presence of macrophages leading to a continuous production of fibrotic material [7]. The literature reported another histological exam performed on a patient with a DNAJB11 pathogenic variant, showing the presence of tubular cysts and moderate arteriosclerosis, but much less interstitial fibrosis [8]. The contribution of a multicentric cohort in this direction could better explicate the real histological phenotype.

References:
1. Shen Y, Hendershot LM. ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. Mol Biol Cell. 2005 Jan;16(1):40-50.
2. Huynh VT, Audrezet MP, Sayer JA, et al. Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease. Kidney Int. 2020 Aug;98(2):476-487.
3. Cornec-Le Gall E, Torres VE, Harris PC. Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases. J Am Soc Nephrol. 2018 Jan;29(1):13-23.
4. Fedeles SV, Gallagher AR, Somlo S. Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol Med. 2014 May;20(5):251-60.
5. Cornec-Le Gall E, Olson RJ, Besse W, et al. Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. Am J Hum Genet. 2018 May 3;102(5):832-844.
6. Pisani I, Allinovi M, Palazzo V, et al. More dissimilarities than affinities between DNAJB11-PKD and ADPKD. Clin Kidney J. 2022 Jun;15(6):1179-1187.
7. Aiello V, Ciurli F, Conti A, et al. DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort. Genes (Basel). 2023 Dec 19;15(1).
8. Wilson GJ, Wood S, Patel C, et al. DNAJB11-Related Atypical ADPKD in a Kidney Transplant Donor. Kidney Int Rep. 2020 Aug;5(8):1363-1366.

The description of new phenotypes related to new mutations is essential to define the best assessment possible. A DNAJB11 pathogenic variant results in a really peculiar cystic phenotype and patients not only present characteristics related to ADPKD, but also seems to face hyperuricemia, Type 2 Diabetes Mellitus and nephrolithiasis, that are usually more present in patients with ADTKD. At the moment, the cohorts assessed for this type of mutation are few and registry data have not been collected yet. The study of these features on a wider cohort could significantly increase the statistical power of clinical data, and could be an important opportunity to better understand the disease resulting from this mutation. It could also help to identify centres with a consistent number of affected patients, potentially creating a European network related to this specific mutation.We are currently starting a new research project, willing to analyse the role of mitochondria affected patients' cells. Serum, urine and tissue samples will be collected and analysed, hoping to find new insights on the pathophysiology of the disease. The contribution of affected patients from other centres could help to better define the research outcomes.

The main inclusion criteria is for patients to have a mutation in DNAJB11.

Useful data that can be collected from the registry are:

• clinical data, including episodes of renal colic, gout attacks, diagnosis of Type 2 Diabetes Mellitus
• laboratory data, including eGFR, creatinine, AST, ALT and others
• imaging data, including abdomen ultrasound and MRI, echocardiography (looking for valvulopathies), brain MRI (looking for aneurysms).

Renal function data can be useful to calculate the eGFR decline and the age at ESRD, to define the disease progression of this particular population of affected patients.

Serum and urine samples could be collected to study the mitochondrial activity.

We would need the already listed data for the patients' registration in the ERKReg and their subsequent visits. This would be necessary for the creation of a subregistry including all patients with a pathogenic variant in DNAJB11 allowing us to better describe the genotype-phenotype relation in affected subjects.

Irene Capelli  - email:  irene.capelli4@unibo.it