Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease

Apple, Benjamin; Sartori, Gino; Moore, Bryn; Chintam, Kiran; Singh, Gurmukteshwar; Anand, Prince Mohan; Strande, Natasha T.; Mirshahi, Tooraj; Triffo, William; Chang, Alexander R.

doi:10.1016/j.kint.2022.11.025

Cited by 13 publications

(22 citation statements)

References 26 publications

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“…No evolution to KF has been described. 10 Bilateral cysts, normal kidney size. 10 May cause polycystic liver disease.…”

Section: Alg8mentioning

confidence: 99%

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Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report

Kachmar,

El-Haffaf,

Bollée

2023

Can J Kidney Health Dis

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Rationale: Due to next-generation sequencing, variants in new genes such as DNAJB11 are recently being identified as causing atypical autosomal dominant polycystic kidney disease (ADPKD). It is important to describe phenotypes associated with these variants in order to increase awareness among clinicians, especially since genetic variability affects ADPKD severity. Presenting Concerns of the Patient: We describe a 55-year-old female patient of Haitian origin who presented with slowly deteriorating kidney function, microscopic hematuria, proteinuria, enlarged kidneys with innumerable small cysts, and a family history of chronic kidney disease and cysts. The phenotype was atypical for ADPKD caused by PKD1 or PKD2 variants, since cysts were of small size, kidneys were only moderately enlarged, and the patient had no extra-renal involvement suggestive of typical ADPKD such as liver cysts, pancreatic cysts, cranial aneurysms, or cardiac abnormalities. Diagnoses: A panel of genes was analyzed by next-generation massive sequencing techniques, including DNAJB11, DZIP1L, GANAB, HNF1B, PKD1, PKD2, and PKHD1. Genetic testing revealed a heterozygous variant in the DNAJB11 gene (c.123 dup), which is predicted to result in premature protein termination (p. Lys42*) and was classified by the laboratory as likely pathogenic. Interventions: She was treated with candesartan 16 mg once daily to address her proteinuria. Outcomes: At the time of the most recent follow-up, her proteinuria has increased, and her kidney function continues to slowly deteriorate. Teaching Points: DNAJB11 variants are a rare cause of atypical ADPKD. It is important to recognize the clinical features that help distinguish DNAJB11 from PKD1 and PKD2 variants. Atypical ADPKD due to DNAJB11 variants is usually characterized by small cysts, normal kidney size, proteinuria, progressive chronic kidney disease, and phenotypic overlap with autosomal dominant tubulointerstitial kidney disease (ADTKD). It may, however, present itself with enlarged kidneys as was seen in our patient. Genetic testing should be offered whenever a patient presents atypical features of ADPKD, which also requires increased awareness among clinicians regarding the various phenotypes of atypical ADPKD.

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“…No evolution to KF has been described. 10 Bilateral cysts, normal kidney size. 10 May cause polycystic liver disease.…”

Section: Alg8mentioning

confidence: 99%

“…10 Bilateral cysts, normal kidney size. 10 May cause polycystic liver disease. 10 Possible association with nephrolithiasis 10 .…”

Section: Alg8mentioning

confidence: 99%

Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report

Kachmar,

El-Haffaf,

Bollée

2023

Can J Kidney Health Dis

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“…The folding and assembly of these large membrane proteins require the assistance of molecular chaperones and glycosylating proteins in the endoplasmic reticulum (ER) (6,7). Atypical forms of ADPKD are caused by mutations in genes encoding ER-resident proteins including GANAB, ALG5, ALG8, and ALG9 (8)(9)(10)(11)(12). Loss of function of the respective ER proteins impairs PC1 maturation and trafficking, which has been proposed as a mechanism causing cyst formation in these rare forms of ADPKD (13).…”

Section: Introductionmentioning

confidence: 99%

The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

Busch,

Neubauer,

Schmitt

et al. 2024

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the genes PKD1 and PKD2, encoding the membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). PC1 and PC2 form a receptor-ion channel complex that is required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation from epithelial cells of all nephron segments. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident proteins through pathogenic mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an endoplasmic reticulum (ER) co-chaperone associated with atypical ADPKD. Mouse models with constitutive and conditional Dnajb11 inactivation as well as Dnajb11-deficient renal epithelial cells were generated to investigate the genetic mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation influences disease severity. Furthermore, impaired PC1 cleavage is identified as a potential mechanism underlying DNAJB11-dependent cyst formation. Quantitative proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, which may help to better understand phenotypic differences between different forms of ADPKD.

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“…ADPKD is the most common (approximately 1:1000) and is typically adult-onset; PKD1 (approximately 79%) and PKD2 (approximately 15%) are the major genes, but mutations to at least six other loci are minor causes (ALG5, ALG8, ALG9, GANAB, DNAJB11, and IFT140). [3][4][5][6][7][8][9][10][11] PKD1 and PKD2 encode polycystin-1 and -2 (PC1 and PC2), which form a functional complex at the primary cilium. Within ADPKD, there is considerable phenotypic heterogeneity ranging from limited cyst development and normal kidney function in old age to very early-onset disease, including neonatal lethality, with genic and allelic factors important.…”

Section: Introductionmentioning

confidence: 99%

Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing

Sieben

Harris

2023

Kidney360

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Polycystic kidney diseases (PKDs) are genetic disorders characterized by the formation and expansion of numerous fluid-filled renal cysts, damaging normal parenchyma, and often leading to kidney failure (KF). Although, PKDs comprise a broad range of different diseases, with substantial genetic and phenotypic heterogeneity, an association with primary cilia represents a common theme. Great strides have been made in the identification of causative genes, furthering our understanding of the genetic complexity and disease mechanisms, but only one therapy so far has shown success in clinical trials and advanced to FDA approval. A key step in understanding disease pathogenesis and testing potential therapeutics is developing orthologous experimental models that accurately recapitulate the human phenotype. This has been particularly important for PKD because cellular models have been of limited value, however, the advent of organoid usage has expanded capabilities in this area but does not negate the need for whole organism models where renal function can be assessed. Animal model generation is further complicated in the most common disease type, autosomal dominant PKD (ADPKD), by homozygous lethality and a very limited cystic phenotype in heterozygotes, while for autosomal recessive PKD (ARPKD), mouse models have a delayed and modest kidney disease, in contrast to humans. However, for ADPKD, the use of conditional/inducible and dosage models have resulted in some of the best disease models in Nephrology. These have been employed to help understand pathogenesis, facilitate genetic interaction studies, and to perform preclinical testing. Whereas, for ARPKD, employing alternative species and digenic models has partially overcome these deficiencies. Here, we review the experimental models that are currently available and most valuable for therapeutic testing in PKD, their applications, success in preclinical trials, advantages and limitations, and where further improvements are needed.

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Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease

Cited by 13 publications

References 26 publications

Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report

Atypical ADPKD Due to a DNAJB11 Pathogenic Variant: An Educational Case Report

The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing

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