TY - JOUR
T1 - Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis
AU - Genomics England Research Consortium
AU - The Genkyst Study Group
AU - Lemoine, Hugo
AU - Raud, Loann
AU - Foulquier, François
AU - Sayer, John A.
AU - Lambert, Baptiste
AU - Olinger, Eric
AU - Lefèvre, Siriane
AU - Knebelmann, Bertrand
AU - Harris, Peter C.
AU - Trouvé, Pascal
AU - Desprès, Aurore
AU - Duneau, Gabrielle
AU - Matignon, Marie
AU - Poyet, Anais
AU - Jourde-Chiche, Noémie
AU - Guerrot, Dominique
AU - Lemoine, Sandrine
AU - Seret, Guillaume
AU - Barroso-Gil, Miguel
AU - Bingham, Coralie
AU - Gilbert, Rodney
AU - Le Meur, Yannick
AU - Audrézet, Marie Pierre
AU - Cornec-Le Gall, Emilie
N1 - Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/8/4
Y1 - 2022/8/4
N2 - Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.
AB - Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.
KW - ALG5
KW - N-linked glycosylation
KW - autosomal dominant tubulo-interstitial kidney disease
KW - autosomal-dominant polycystic kidney disease
KW - renal insufficiency
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U2 - 10.1016/j.ajhg.2022.06.013
DO - 10.1016/j.ajhg.2022.06.013
M3 - Article
C2 - 35896117
AN - SCOPUS:85135600200
SN - 0002-9297
VL - 109
SP - 1484
EP - 1499
JO - American journal of human genetics
JF - American journal of human genetics
IS - 8
ER -