ALg9 mutation carriers develop kidney and liver cysts

Whitney Besse, Alex R. Chang, Jonathan Z. Luo, William J. Triffo, Bryn S. Moore, Ashima Gulati, Dustin N. Hartzel, Shrikant Mane, Vicente E. Torres, Stefan Somlo, Tooraj Mirshahi

Research output: Contribution to journalArticle

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Abstract

Background Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). MethodsWeused whole-exomesequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Results Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. Conclusions ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.

Original languageEnglish (US)
Pages (from-to)2091-2102
Number of pages12
JournalJournal of the American Society of Nephrology
Volume30
Issue number11
DOIs
StatePublished - Jan 1 2019

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Autosomal Dominant Polycystic Kidney
Cysts
Kidney
Mutation
Liver
Endoplasmic Reticulum
Genes
Exome
Phenotype
Carrier State
Polycystic Kidney Diseases
Proteins
Kidney Diseases
Genetic Association Studies
Mannose
Glycosylation
Population
Polysaccharides
Membrane Proteins
polycystic kidney disease 1 protein

ASJC Scopus subject areas

  • Nephrology

Cite this

Besse, W., Chang, A. R., Luo, J. Z., Triffo, W. J., Moore, B. S., Gulati, A., ... Mirshahi, T. (2019). ALg9 mutation carriers develop kidney and liver cysts. Journal of the American Society of Nephrology, 30(11), 2091-2102. https://doi.org/10.1681/ASN.2019030298

ALg9 mutation carriers develop kidney and liver cysts. / Besse, Whitney; Chang, Alex R.; Luo, Jonathan Z.; Triffo, William J.; Moore, Bryn S.; Gulati, Ashima; Hartzel, Dustin N.; Mane, Shrikant; Torres, Vicente E.; Somlo, Stefan; Mirshahi, Tooraj.

In: Journal of the American Society of Nephrology, Vol. 30, No. 11, 01.01.2019, p. 2091-2102.

Research output: Contribution to journalArticle

Besse, W, Chang, AR, Luo, JZ, Triffo, WJ, Moore, BS, Gulati, A, Hartzel, DN, Mane, S, Torres, VE, Somlo, S & Mirshahi, T 2019, 'ALg9 mutation carriers develop kidney and liver cysts', Journal of the American Society of Nephrology, vol. 30, no. 11, pp. 2091-2102. https://doi.org/10.1681/ASN.2019030298
Besse W, Chang AR, Luo JZ, Triffo WJ, Moore BS, Gulati A et al. ALg9 mutation carriers develop kidney and liver cysts. Journal of the American Society of Nephrology. 2019 Jan 1;30(11):2091-2102. https://doi.org/10.1681/ASN.2019030298
Besse, Whitney ; Chang, Alex R. ; Luo, Jonathan Z. ; Triffo, William J. ; Moore, Bryn S. ; Gulati, Ashima ; Hartzel, Dustin N. ; Mane, Shrikant ; Torres, Vicente E. ; Somlo, Stefan ; Mirshahi, Tooraj. / ALg9 mutation carriers develop kidney and liver cysts. In: Journal of the American Society of Nephrology. 2019 ; Vol. 30, No. 11. pp. 2091-2102.
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abstract = "Background Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). MethodsWeused whole-exomesequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Results Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88{\%}) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88{\%}) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. Conclusions ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.",
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T1 - ALg9 mutation carriers develop kidney and liver cysts

AU - Besse, Whitney

AU - Chang, Alex R.

AU - Luo, Jonathan Z.

AU - Triffo, William J.

AU - Moore, Bryn S.

AU - Gulati, Ashima

AU - Hartzel, Dustin N.

AU - Mane, Shrikant

AU - Torres, Vicente E.

AU - Somlo, Stefan

AU - Mirshahi, Tooraj

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). MethodsWeused whole-exomesequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Results Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. Conclusions ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.

AB - Background Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). MethodsWeused whole-exomesequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Results Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. Conclusions ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.

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