Dataset Information

Challenging Disease Ontology by Instances of Atypical PKHD1 and PKD1 Genetics.

ABSTRACT:

Background

Autosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance.

Methods

Next-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping.

Results

Three unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance.

Conclusion

By this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general.

SUBMITTER: de Fallois J

PROVIDER: S-EPMC8267867 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Autosomal recessive polycystic kidney disease (ARPKD) results from mutations in the human PKHD1 gene. Both this gene, and its mouse ortholog, Pkhd1, are primarily expressed in renal and biliary ductal structures. The mouse protein product, fibrocystin/polyductin complex (FPC), is a 445-kDa protein encoded by a 67-exon transcript that spans >500 kb of genomic DNA. In the current study, we observed multiple alternatively spliced Pkhd1 transcripts that varied in size and exon composition in embryonic mouse kidney, liver, and placenta samples, as well as among adult mouse pancreas, brain, heart, lung, testes, liver, and kidney. Using reverse transcription PCR and RNASeq, we identified 22 novel Pkhd1 kidney transcripts with unique exon junctions. Various mechanisms of alternative splicing were observed, including exon skipping, use of alternate acceptor/donor splice sites, and inclusion of novel exons. Bioinformatic analyses identified, and exon-trapping minigene experiments validated, consensus binding sites for serine/arginine-rich proteins that modulate alternative splicing. Using site-directed mutagenesis, we examined the functional importance of selected splice enhancers. In addition, we demonstrated that many of the novel transcripts were polysome bound, thus likely translated. Finally, we determined that the human PKHD1 R760H missense variant alters a splice enhancer motif that disrupts exon splicing in vitro and is predicted to truncate the protein. Taken together, these data provide evidence of the complex transcriptional regulation of Pkhd1/PKHD1 and identified motifs that regulate its splicing. Our studies indicate that Pkhd1/PKHD1 transcription is modulated, in part by intragenic factors, suggesting that aberrant PKHD1 splicing represents an unappreciated pathogenic mechanism in ARPKD. Key messages: Multiple mRNA transcripts are generated for Pkhd1 in renal tissues Pkhd1 transcription is modulated by standard splice elements and effectors Mutations in splice motifs may alter splicing to generate nonfunctional peptides.

Project description:BACKGROUND: Caused by intracellular Gram-negative bacteria Brucella spp., brucellosis is the most common bacterial zoonotic disease. Extensive studies in brucellosis have yielded a large number of publications and data covering various topics ranging from basic Brucella genetic study to vaccine clinical trials. To support data interoperability and reasoning, a community-based brucellosis-specific biomedical ontology is needed. RESULTS: The Brucellosis Ontology (IDOBRU: http://sourceforge.net/projects/idobru), a biomedical ontology in the brucellosis domain, is an extension ontology of the core Infectious Disease Ontology (IDO-core) and follows OBO Foundry principles. Currently IDOBRU contains 1503 ontology terms, which includes 739 Brucella-specific terms, 414 IDO-core terms, and 350 terms imported from 10 existing ontologies. IDOBRU has been used to model different aspects of brucellosis, including host infection, zoonotic disease transmission, symptoms, virulence factors and pathogenesis, diagnosis, intentional release, vaccine prevention, and treatment. Case studies are typically used in our IDOBRU modeling. For example, diurnal temperature variation in Brucella patients, a Brucella-specific PCR method, and a WHO-recommended brucellosis treatment were selected as use cases to model brucellosis symptom, diagnosis, and treatment, respectively. Developed using OWL, IDOBRU supports OWL-based ontological reasoning. For example, by performing a Description Logic (DL) query in the OWL editor Protégé 4 or a SPARQL query in an IDOBRU SPARQL server, a check of Brucella virulence factors showed that eight of them are known protective antigens based on the biological knowledge captured within the ontology. CONCLUSIONS: IDOBRU is the first reported bacterial infectious disease ontology developed to represent different disease aspects in a formal logical format. It serves as a brucellosis knowledgebase and supports brucellosis data integration and automated reasoning.