Isolated polycystic liver disease genes define effectors of polycystin-1 function

Besse, Whitney; Dong, Ke; Choi, Jungmin; Punia, Sohan; Fedeles, Sorin V.; Choi, Murim; Gallagher, Anna-Rachel; Huang, Emily; Gulati, Ashima; Knight, James; Mane, Shrikant; Tahvanainen, Esa; Tahvanainen, Pia; Sanna‐Cherchi, Simone; Lifton, Richard P.; Watnick, Terry; Pei, York; Torres, Vicente E.; Somlo, Stefan

doi:10.1172/jci90129

Cited by 143 publications

(95 citation statements)

References 65 publications

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“…A lack of PUF60 diminished the expression of the Ca 2+ -sensitive OGDH isoform ( Supplementary Figure S6 ), which could render the oxoglutarate dehydrogenase complex dysfunctional, contributing to metabolic and neurological symptoms ( Supplementary Table S9 ). Polycystic kidneys, also a part of the PD syndrome ( 32 , 33 ), were recently associated with a loss of GANAB (subunit α of glucosidase II) ( 125 , 126 ), which is required for maturation of polycystin proteins and their localization to the cell surface ( 125 ). Both animal and S. pombe mutants were viable (125 and refs.…”

Section: Discussionmentioning

confidence: 99%

PUF60-activated exons uncover altered 3′ splice-site selection by germline missense mutations in a single RRM

Královičová

Sevcikova

Stejskalová

et al. 2018

Nucleic Acids Research

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PUF60 is a splicing factor that binds uridine (U)-rich tracts and facilitates association of the U2 small nuclear ribonucleoprotein with primary transcripts. PUF60 deficiency (PD) causes a developmental delay coupled with intellectual disability and spinal, cardiac, ocular and renal defects, but PD pathogenesis is not understood. Using RNA-Seq, we identify human PUF60-regulated exons and show that PUF60 preferentially acts as their activator. PUF60-activated internal exons are enriched for Us upstream of their 3′ splice sites (3′ss), are preceded by longer AG dinucleotide exclusion zones and more distant branch sites, with a higher probability of unpaired interactions across a typical branch site location as compared to control exons. In contrast, PUF60-repressed exons show U-depletion with lower estimates of RNA single-strandedness. We also describe PUF60-regulated, alternatively spliced isoforms encoding other U-bound splicing factors, including PUF60 partners, suggesting that they are co-regulated in the cell, and identify PUF60-regulated exons derived from transposed elements. PD-associated amino-acid substitutions, even within a single RNA recognition motif (RRM), altered selection of competing 3′ss and branch points of a PUF60-dependent exon and the 3′ss choice was also influenced by alternative splicing of PUF60. Finally, we propose that differential distribution of RNA processing steps detected in cells lacking PUF60 and the PUF60-paralog RBM39 is due to the RBM39 RS domain interactions. Together, these results provide new insights into regulation of exon usage by the 3′ss organization and reveal that germline mutation heterogeneity in RRMs can enhance phenotypic variability at the level of splice-site and branch-site selection.

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Section: Discussionmentioning

confidence: 99%

PUF60-activated exons uncover altered 3′ splice-site selection by germline missense mutations in a single RRM

Královičová

Sevcikova

Stejskalová

et al. 2018

Nucleic Acids Research

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“…LRP5 encodes low‐density lipoprotein receptor–related protein 5, which functions as a coreceptor for Frizzled in the canonical Wnt signaling pathway. Despite the fact that Besse et al did not discover any loss‐of‐function LRP5 mutations in the cohort of analyzed patients, missense variants in LRP5 were found to coexist with PKHD1 variants, suggesting that interaction of these two genes may contribute to hepatic cystogenesis in patients with mutated PKHD1 .…”

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confidence: 81%

“…In addition, two other genes, LRP5 and GANAB , have been implicated in the development of ADPLD . Recently, analyzing a cohort of 102 patients with no mutations in PRKCSH and SEC63 , Besse et al found two novel genes, ALG8 and SEC61B , to be also responsible for hepatic cystogenesis in isolated PLD (Fig. A).…”

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confidence: 99%

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Polycystic liver disease: The interplay of genes causative for hepatic and renal cystogenesis

Masyuk

LaRusso

2018

Hepatology

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“… [6] , [7] , [8] , [9] The first 2 genes associated with ADPLD, PRKCSH and SEC63 , were identified in families characterised by relatively severe PLD in the absence of or with very few renal cysts. [10] , [11] , [12] Additional genes have more recently been identified to be variably associated with ADPLD, [13] , [14] , [15] , [16] , [17] , [18] , [19] but affected patients frequently exhibit renal cysts as well, pointing to a significant overlap between ADPLD and ADPKD. 20 …”

Section: Introductionmentioning

confidence: 99%

Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county

et al. 2020

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Background & Aims Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, the frequency of truncating mutations to ADPLD genes in large, population sequencing databases is 1:496. With the increasing use of abdominal imaging, incidental detection of hepatic cysts and ADPLD has become more frequent. The present study was performed to ascertain the incidence and point prevalence of ADPLD in Olmsted County, MN, USA, and how these are impacted by the increasing utilisation of abdominal imaging. Methods The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center were searched to identify all subjects meeting diagnostic criteria for definite, likely, or possible ADPLD. Annual incidence rates were calculated using incident cases during 1980–2016 as numerator, and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator, and age- and sex-specific estimates of the population of Olmsted County on 1 January 2010 as denominator. Results The incidence rate and point prevalence of combined definite and likely ADPLD were 1.01 per 100,000 person-years and 9.5 per 100,000 population, respectively. Only 15 of 35 definite and likely incident ADPLD cases had received a diagnostic code, and only 8 had clinically significant hepatomegaly. The incidence rates were much higher when adding possible cases, mainly identified through radiology databases, particularly in recent years and in older patients because of the increased utilisation of imaging studies. Conclusions Clinically significant isolated ADPLD is a rare disease with a prevalence <1:10,000 population. The overall prevalence of ADPLD, however, to a large extent not clinically significant, is likely much higher and closer to the reported genetic prevalence. Lay summary Isolated autosomal-dominant polycystic liver disease (ADPLD) is generally considered a rare disease. However, we demonstrate that it is a relatively common disease, which is rarely (<1:10,000 population) clinically significant.

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Isolated polycystic liver disease genes define effectors of polycystin-1 function

Cited by 143 publications

References 65 publications

PUF60-activated exons uncover altered 3′ splice-site selection by germline missense mutations in a single RRM

PUF60-activated exons uncover altered 3′ splice-site selection by germline missense mutations in a single RRM

Polycystic liver disease: The interplay of genes causative for hepatic and renal cystogenesis

Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county

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