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Published on: June 23, 2015
DNAJB11 Mutation in ADPKD Patients: Clinical Characteristics in a Monocentric Cohort
Valeria Aiello1,2, Francesca Ciurli1, Amalia Conti3
1Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
Insights
Genetic variants in the DNAJB11 gene are linked to kidney disease, presenting features of both Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD). This suggests DNAJB11 mutations cause an overlap syndrome.
Area of Science:
- Nephrology
- Medical Genetics
- Ciliary Biology
Background:
- Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a progressive kidney disorder caused by genetic mutations.
- While PKD1 and PKD2 are the primary genes, approximately 7% of ADPKD cases remain genetically unresolved.
- DNAJB11 has emerged as a gene associated with renal cystic diseases, but its full phenotypic spectrum is still being defined.
Purpose of the Study:
- To investigate the role of DNAJB11 variants in families with unresolved ADPKD.
- To characterize the clinical and imaging findings in patients with DNAJB11 mutations.
- To determine if DNAJB11 mutations contribute to an overlap phenotype between ADPKD and ADTKD.
Main Methods:
- Collected clinical and imaging data from 4 families with heterozygous DNAJB11 variants.
- Classified DNAJB11 variants as Likely Pathogenetic (LP) or Variants of Uncertain Significance (VUS).
- Reviewed kidney biopsy findings, including interstitial fibrosis, and associated comorbidities like hyperuricemia and diabetes.
Main Results:
- Three of the four families had likely pathogenetic DNAJB11 variants.
- Patients exhibited ADPKD characteristics alongside ADTKD features such as hyperuricemia, diabetes, and chronic interstitial fibrosis.
- Kidney biopsy in one patient revealed significant interstitial fibrosis.
Conclusions:
- DNAJB11 mutations are implicated in a subset of genetically unresolved ADPKD cases.
- The DNAJB11 phenotype appears to be an overlap syndrome, sharing features with both ADPKD and ADTKD.
- Further research is needed to fully elucidate the spectrum and mechanisms of DNAJB11-associated kidney disease.
Abstract:
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.
