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Rationale: The role of the innate immune system in polycystic liver disease (PLD) has been underexplored despite its potential importance in disease progression. This study explores the innate immune response in PLD patients by analyzing cytokine production of peripheral blood mononuclear cells (PBMCs) in response to various pathogens compared to healthy controls., Methods: Samples were collected from patients with ADPLD or ADPKD and PLD. PBMCs were isolated and stimulated with LPS (1 ng), LPS (10 ng), E. coli, K. pneumoniae, S. aureus, and C. albicans. ELISA was used to measure TNF, IL-1β, IL-1Ra, IL-6, and IL-8 concentrations after 24 hours, and IL-17, IL-22, and IFNγ concentrations after 7 days. Control samples were matched for age and gender., Results: 104 patients and 12 controls were included. PLD patients showed consistent increased IL-6 concentrations compared to controls. Other cytokine levels varied per stimulus. Controls showed higher IL-8 and TNF concentrations in response to Gram-negative bacteria, while PLD patients showed higher IL-1β and IL-1Ra levels in response to S. aureus and C. albicans. No clear differences were found in IL-17, IL-22, and IFN-γ concentrations after 7 days. These observed differences were independent of demographic and clinical parameters., Conclusion: Compared to healthy controls, the PLD patients innate immune system shows an altered response when stimulated by various pathogens. These findings underscore the importance of further investigation into the underlying mechanisms as this might help our understanding disease progression and be a potential target for new therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35 ) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery.

α-1,2-mannosyltransferase ( ALG9 ) germline variants are linked to autosomal dominant polycystic kidney disease (ADPKD). Many individuals affected with ADPKD possess polycystic livers as a common extrarenal manifestation. We performed whole exome sequencing in a female with autosomal dominant polycystic liver disease (ADPLD) without kidney cysts and established the presence of a heterozygous missense variant (c.677G>C p.(Gly226Ala)) in ALG9 . In silico pathogenicity prediction and 3D protein modeling determined this variant as pathogenic. Loss of heterozygosity is regularly seen in liver cyst walls. Immunohistochemistry indicated the absence of ALG9 in liver tissue from this patient. ALG9 expression was absent in cyst wall lining from ALG9 - and PRKCSH -caused ADPLD patients but present in the liver cyst lining derived from an ADPKD patient with a PKD2 variant. Thus, heterozygous pathogenic variants in ALG9 are also associated with ADPLD. Somatic loss of heterozygosity of the ALG9 enzyme was seen in the ALG9 patient but also in ADPLD patients with a different genetic background. This expanded the phenotypic spectrum of ADPLD to ALG9 .

Protein-truncating variants in α-1,3-glucosyltransferase ( ALG8 ) are a risk factor for a mild cystic kidney disease phenotype. The association between these variants and liver cysts is limited. We aim to identify pathogenic ALG8 variants in our cohort of autosomal dominant polycystic liver disease (ADPLD) individuals. In order to fine-map the phenotypical spectrum of pathogenic ALG8 variant carriers, we performed targeted ALG8 screening in 478 ADPLD singletons, and exome sequencing in 48 singletons and 4 patients from two large ADPLD families. Eight novel and one previously reported pathogenic variant in ALG8 were discovered in sixteen patients. The ALG8 clinical phenotype ranges from mild to severe polycystic liver disease, and from innumerable small to multiple large hepatic cysts. The presence of <5 renal cysts that do not affect renal function is common in this population. Three-dimensional homology modeling demonstrated that six variants cause a truncated ALG8 protein with abnormal functioning, and one variant is predicted to destabilize ALG8. For the seventh variant, immunostaining of the liver tissue showed a complete loss of ALG8 in the cystic cells. ALG8 -associated ADPLD has a broad clinical spectrum, including the possibility of developing a small number of renal cysts. This broadens the ADPLD genotype-phenotype spectrum and narrows the gap between liver-specific ADPLD and kidney-specific ADPKD.

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10., (© 2022. The Author(s).)

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants., Methods: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing., Results: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies., Conclusion: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patients are frequently not genetically screened as knowledge about the genotype-phenotype correlation is currently limited. This paper will clarify the essence of genetic testing in ADPLD patients., (Copyright © 2021 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)