Isolated polycystic liver disease genes define effectors of polycystin-1 function
Whitney Besse, … , Vicente E. Torres, Stefan Somlo
Whitney Besse, … , Vicente E. Torres, Stefan Somlo
Published April 4, 2017
Citation Information: J Clin Invest. 2017;127(5):1772-1785. https://doi.org/10.1172/JCI90129.
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Research Article Genetics Nephrology

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

Abstract

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

Authors

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

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Figure 6

Schematic of the function of the PCLD genes in the ER protein biogenesis pathway.

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Schematic of the function of the PCLD genes in the ER protein biogenesis...
The PCLD genes are numbered 1–5. Lipid-linked oligosaccharide precursors of N-linked glycans are initially assembled on dolichol on the cytoplasmic aspect of the ER membrane. These are flipped into the ER lumen, where ALG8 (1) catalyzes the addition of the second glucose residue. Nascent polypeptides undergo cotranslational translocation via the SEC61 translocation pore that is composed of α, β (2), and γ subunits and is associated with SEC62. SEC63 (3) and ERJ1 act in concert with the major ER HSP70 chaperone BiP to facilitate this translocation process. Oligosaccharyl transferase (OST) catalyzes the attachment of the glycan moiety to asparagine residues. Glucosidase I removes the outermost glucose before glucosidase II, composed of GIIα (4) and GIIβ (5) subunits, removes the second glucose. This step is necessary for the nascent peptide to enter the calnexin (CNX)/calreticulin (CRT) protein folding and quality control cycle. Glucosidase II (4, 5) subsequently removes the innermost glucose from the N-linked glycan, allowing for exit from the CNX/CRT cycle. If the protein has attained its properly folded conformation, it proceeds along the secretory pathway. Misfolded proteins are recognized and reglucosylated by UGGT, allowing for more time in the folding environment of the CNX/CRT cycle. Eventually, proteins that fail to fold properly undergo ER-associated degradation by retrotranslocation through the SEC61 translocon complex into the cytoplasmic compartment, where they are degraded by the proteasome.