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

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 Torres, Stefan Somlo

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1772-1785
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number5
DOIs
StatePublished - May 1 2017

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Genes
Cysts
Mutation
Autosomal Recessive Polycystic Kidney
Exome
Autosomal Dominant Polycystic Kidney
Endoplasmic Reticulum
Polycystic liver disease
polycystic kidney disease 1 protein
Molecular Biology
Proteins
Genome
Kidney
Cell Line
Liver

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Besse, W., Dong, K., Choi, J., Punia, S., Fedeles, S. V., Choi, M., ... Somlo, S. (2017). Isolated polycystic liver disease genes define effectors of polycystin-1 function. Journal of Clinical Investigation, 127(5), 1772-1785. https://doi.org/10.1172/JCI90129

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 B.; Gulati, Ashima; Knight, James; Mane, Shrikant; Tahvanainen, Esa; Tahvanainen, Pia; Sanna-Cherchi, Simone; Lifton, Richard P.; Watnick, Terry; Pei, York P.; Torres, Vicente; Somlo, Stefan.

In: Journal of Clinical Investigation, Vol. 127, No. 5, 01.05.2017, p. 1772-1785.

Research output: Contribution to journalArticle

Besse, W, Dong, K, Choi, J, Punia, S, Fedeles, SV, Choi, M, Gallagher, AR, Huang, EB, Gulati, A, Knight, J, Mane, S, Tahvanainen, E, Tahvanainen, P, Sanna-Cherchi, S, Lifton, RP, Watnick, T, Pei, YP, Torres, V & Somlo, S 2017, 'Isolated polycystic liver disease genes define effectors of polycystin-1 function', Journal of Clinical Investigation, vol. 127, no. 5, pp. 1772-1785. https://doi.org/10.1172/JCI90129
Besse, Whitney ; Dong, Ke ; Choi, Jungmin ; Punia, Sohan ; Fedeles, Sorin V. ; Choi, Murim ; Gallagher, Anna Rachel ; Huang, Emily B. ; Gulati, Ashima ; Knight, James ; Mane, Shrikant ; Tahvanainen, Esa ; Tahvanainen, Pia ; Sanna-Cherchi, Simone ; Lifton, Richard P. ; Watnick, Terry ; Pei, York P. ; Torres, Vicente ; Somlo, Stefan. / Isolated polycystic liver disease genes define effectors of polycystin-1 function. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 5. pp. 1772-1785.
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