Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity

Xiangchen Gu; Hongliu Yang; Xin Sheng; Yi-An Ko; Chengxiang Qiu; Jihwan Park; Shizheng Huang; Rachel Kember; Renae L. Judy; Joseph Park; Scott M. Damrauer; Girish Nadkarni; Ruth J. F. Loos; Vy Thi Ha My; Kumardeep Chaudhary; Erwin P. Bottinger; Ishan Paranjpe; Aparna Saha; Christopher Brown; Shreeram Akilesh; Adriana M. Hung; Matthew Palmer; Aris Baras; John D. Overton; Jeffrey Reid; Marylyn Ritchie; Daniel J. Rader; Katalin Susztak

doi:10.1126/scitranslmed.aaz1458

Research ArticleKidney Disease

Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity

View ORCID ProfileXiangchen Gu ¹,²,*,
View ORCID ProfileHongliu Yang¹,³,*,
View ORCID ProfileXin Sheng¹,*,
Yi-An Ko¹,
View ORCID ProfileChengxiang Qiu¹,
View ORCID ProfileJihwan Park¹,
View ORCID ProfileShizheng Huang¹,
View ORCID ProfileRachel Kember⁴,
Renae L. Judy⁵,
View ORCID ProfileJoseph Park⁴,⁶,
Scott M. Damrauer ⁵,⁷,
Girish Nadkarni⁸,⁹,¹⁰,
View ORCID ProfileRuth J. F. Loos⁹,
View ORCID ProfileVy Thi Ha My⁹,
View ORCID ProfileKumardeep Chaudhary⁹,
View ORCID ProfileErwin P. Bottinger⁹,¹⁰,
View ORCID ProfileIshan Paranjpe⁹,
View ORCID ProfileAparna Saha⁹,
View ORCID ProfileChristopher Brown⁶,
View ORCID ProfileShreeram Akilesh¹¹,
View ORCID ProfileAdriana M. Hung ¹²,¹³,
Matthew Palmer¹⁴,
Aris Baras¹⁵,
View ORCID ProfileJohn D. Overton¹⁵,
View ORCID ProfileJeffrey Reid¹⁵,
View ORCID ProfileMarylyn Ritchie⁴,⁶,
Daniel J. Rader ¹,⁴,⁶ and
View ORCID ProfileKatalin Susztak ¹,⁶,†

¹Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
²Division of Nephrology, Yueyang Hospital of Integrative Traditional Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
³Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China.
⁴Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
⁵Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
⁶Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
⁸Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰The Hasso Plattner Institute of Digital Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹Department of Pathology, University of Washington, Seattle, WA 98195, USA.
¹²Nashville VA Medical Center, Nashville, TN 37212, USA.
¹³Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
¹⁴Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁵Regeneron Genetics Center (RGC), 777 Old Saw Mill River Rd., Tarrytown, NY 10591, USA.

↵†Corresponding author. Email: ksusztak{at}pennmedicine.upenn.edu

↵* These authors contributed equally to this work.

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Science Translational Medicine 13 Jan 2021:
Vol. 13, Issue 576, eaaz1458
DOI: 10.1126/scitranslmed.aaz1458

Xiangchen Gu

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

2Division of Nephrology, Yueyang Hospital of Integrative Traditional Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.

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Hongliu Yang

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

3Division of Nephrology, West China Hospital of Sichuan University, Chengdu 610041, China.

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Xin Sheng

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Yi-An Ko

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Chengxiang Qiu

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Jihwan Park

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Shizheng Huang

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Rachel Kember

4Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Renae L. Judy

5Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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Joseph Park

4Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

6Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Scott M. Damrauer

5Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

7Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA.

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Girish Nadkarni

8Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

10The Hasso Plattner Institute of Digital Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Ruth J. F. Loos

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Vy Thi Ha My

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Kumardeep Chaudhary

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Erwin P. Bottinger

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

10The Hasso Plattner Institute of Digital Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Ishan Paranjpe

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Aparna Saha

9The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

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Christopher Brown

6Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Shreeram Akilesh

11Department of Pathology, University of Washington, Seattle, WA 98195, USA.

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Adriana M. Hung

12Nashville VA Medical Center, Nashville, TN 37212, USA.

13Vanderbilt Center for Kidney Disease, Vanderbilt University Medical Center, Nashville, TN 37212, USA.

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Matthew Palmer

14Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Aris Baras

15Regeneron Genetics Center (RGC), 777 Old Saw Mill River Rd., Tarrytown, NY 10591, USA.

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John D. Overton

15Regeneron Genetics Center (RGC), 777 Old Saw Mill River Rd., Tarrytown, NY 10591, USA.

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Jeffrey Reid

15Regeneron Genetics Center (RGC), 777 Old Saw Mill River Rd., Tarrytown, NY 10591, USA.

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Marylyn Ritchie

4Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

6Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Daniel J. Rader

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

4Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

6Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Katalin Susztak

1Department of Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

6Department of Genetics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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For correspondence: ksusztak@pennmedicine.upenn.edu

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Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity

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