Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease

Binu Porath, Vladimir G. Gainullin, Emilie Cornec-Le Gall, Elizabeth K. Dillinger, Christina M. Heyer, Katharina Hopp, Marie E. Edwards, Charles D. Madsen, Sarah R. Mauritz, Carly J. Banks, Saurabh Baheti, Bharathi Reddy, José Ignacio Herrero, Jesús M. Bañales, Marie C. Hogan, Velibor Tasic, Terry J. Watnick, Arlene B. Chapman, Cécile Vigneau, Frédéric Lavainne & 5 others Marie Pierre Audrézet, Claude Ferec, Yannick Le Meur, Vicente E. Torres, Peter C. Harris

Research output: Contribution to journalArticle

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is a common, progressive, adult-onset disease that is an important cause of end-stage renal disease (ESRD), which requires transplantation or dialysis. Mutations in PKD1 or PKD2 (∼85% and ∼15% of resolved cases, respectively) are the known causes of ADPKD. Extrarenal manifestations include an increased level of intracranial aneurysms and polycystic liver disease (PLD), which can be severe and associated with significant morbidity. Autosomal-dominant PLD (ADPLD) with no or very few renal cysts is a separate disorder caused by PRKCSH, SEC63, or LRP5 mutations. After screening, 7%-10% of ADPKD-affected and ∼50% of ADPLD-affected families were genetically unresolved (GUR), suggesting further genetic heterogeneity of both disorders. Whole-exome sequencing of six GUR ADPKD-affected families identified one with a missense mutation in GANAB, encoding glucosidase II subunit α (GIIα). Because PRKCSH encodes GIIβ, GANAB is a strong ADPKD and ADPLD candidate gene. Sanger screening of 321 additional GUR families identified eight further likely mutations (six truncating), and a total of 20 affected individuals were identified in seven ADPKD- and two ADPLD-affected families. The phenotype was mild PKD and variable, including severe, PLD. Analysis of GANAB-null cells showed an absolute requirement of GIIα for maturation and surface and ciliary localization of the ADPKD proteins (PC1 and PC2), and reduced mature PC1 was seen in GANAB+/- cells. PC1 surface localization in GANAB-/- cells was rescued by wild-type, but not mutant, GIIα. Overall, we show that GANAB mutations cause ADPKD and ADPLD and that the cystogenesis is most likely driven by defects in PC1 maturation.

Original languageEnglish (US)
Pages (from-to)1193-1207
Number of pages15
JournalAmerican Journal of Human Genetics
Volume98
Issue number6
DOIs
StatePublished - Jun 2 2016
Externally publishedYes

Fingerprint

Autosomal Dominant Polycystic Kidney
Mutation
Proprotein Convertase 2
Exome
Null Lymphocytes
Genetic Heterogeneity
Polycystic liver disease
4-nitrophenyl-alpha-glucosidase
Intracranial Aneurysm
Missense Mutation
Chronic Kidney Failure
Cysts
Dialysis
Transplantation
Morbidity
Phenotype
Kidney
1-dodecylpyridoxal

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Porath, B., Gainullin, V. G., Cornec-Le Gall, E., Dillinger, E. K., Heyer, C. M., Hopp, K., ... Harris, P. C. (2016). Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. American Journal of Human Genetics, 98(6), 1193-1207. https://doi.org/10.1016/j.ajhg.2016.05.004

Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. / Porath, Binu; Gainullin, Vladimir G.; Cornec-Le Gall, Emilie; Dillinger, Elizabeth K.; Heyer, Christina M.; Hopp, Katharina; Edwards, Marie E.; Madsen, Charles D.; Mauritz, Sarah R.; Banks, Carly J.; Baheti, Saurabh; Reddy, Bharathi; Herrero, José Ignacio; Bañales, Jesús M.; Hogan, Marie C.; Tasic, Velibor; Watnick, Terry J.; Chapman, Arlene B.; Vigneau, Cécile; Lavainne, Frédéric; Audrézet, Marie Pierre; Ferec, Claude; Le Meur, Yannick; Torres, Vicente E.; Harris, Peter C.

In: American Journal of Human Genetics, Vol. 98, No. 6, 02.06.2016, p. 1193-1207.

Research output: Contribution to journalArticle

Porath, B, Gainullin, VG, Cornec-Le Gall, E, Dillinger, EK, Heyer, CM, Hopp, K, Edwards, ME, Madsen, CD, Mauritz, SR, Banks, CJ, Baheti, S, Reddy, B, Herrero, JI, Bañales, JM, Hogan, MC, Tasic, V, Watnick, TJ, Chapman, AB, Vigneau, C, Lavainne, F, Audrézet, MP, Ferec, C, Le Meur, Y, Torres, VE & Harris, PC 2016, 'Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease', American Journal of Human Genetics, vol. 98, no. 6, pp. 1193-1207. https://doi.org/10.1016/j.ajhg.2016.05.004
Porath, Binu ; Gainullin, Vladimir G. ; Cornec-Le Gall, Emilie ; Dillinger, Elizabeth K. ; Heyer, Christina M. ; Hopp, Katharina ; Edwards, Marie E. ; Madsen, Charles D. ; Mauritz, Sarah R. ; Banks, Carly J. ; Baheti, Saurabh ; Reddy, Bharathi ; Herrero, José Ignacio ; Bañales, Jesús M. ; Hogan, Marie C. ; Tasic, Velibor ; Watnick, Terry J. ; Chapman, Arlene B. ; Vigneau, Cécile ; Lavainne, Frédéric ; Audrézet, Marie Pierre ; Ferec, Claude ; Le Meur, Yannick ; Torres, Vicente E. ; Harris, Peter C. / Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 6. pp. 1193-1207.
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T1 - Mutations in GANAB, Encoding the Glucosidase IIα Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease

AU - Porath, Binu

AU - Gainullin, Vladimir G.

AU - Cornec-Le Gall, Emilie

AU - Dillinger, Elizabeth K.

AU - Heyer, Christina M.

AU - Hopp, Katharina

AU - Edwards, Marie E.

AU - Madsen, Charles D.

AU - Mauritz, Sarah R.

AU - Banks, Carly J.

AU - Baheti, Saurabh

AU - Reddy, Bharathi

AU - Herrero, José Ignacio

AU - Bañales, Jesús M.

AU - Hogan, Marie C.

AU - Tasic, Velibor

AU - Watnick, Terry J.

AU - Chapman, Arlene B.

AU - Vigneau, Cécile

AU - Lavainne, Frédéric

AU - Audrézet, Marie Pierre

AU - Ferec, Claude

AU - Le Meur, Yannick

AU - Torres, Vicente E.

AU - Harris, Peter C.

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