Isolated polycystic liver disease genes define effectors of polycystin-1 function
| Autor: | Ashima Gulati, Jungmin Choi, Sohan Punia, Richard P. Lifton, Shrikant Mane, Anna Rachel Gallagher, Sorin V. Fedeles, Murim Choi, Simone Sanna-Cherchi, Terry Watnick, Vicente E. Torres, York Pei, James R. Knight, Emily B. Huang, Ke Dong, Whitney Besse, Esa Tahvanainen, Pia Tahvanainen, Stefan Somlo |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Candidate gene 030232 urology & nephrology Autosomal dominant polycystic kidney disease Biology Kidney cysts 03 medical and health sciences 0302 clinical medicine SEC63 Clinical investigation medicine Isolated polycystic liver disease Gene Exome sequencing Polycystin-1 Genetics Effector business.industry PRKCSH Cilium General Medicine medicine.disease Autosomal Recessive Polycystic Kidney Disease 3. Good health 030104 developmental biology 030220 oncology & carcinogenesis Cancer research medicine.symptom Corrigendum business Function (biology) |
| Zdroj: | Journal of Clinical Investigation. 127:1772-1785 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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