INACTIVATING MUTATIONS IN NEDD4L CAUSE LIDDLE SYNDROME WITH NEPHROGENIC-DIABETES-INSIPIDUS AND DEAFNESS (LINDID)

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Abstract Title *

INACTIVATING MUTATIONS IN NEDD4L CAUSE LIDDLE SYNDROME WITH NEPHROGENIC-DIABETES-INSIPIDUS AND DEAFNESS (LINDID)

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Co-author 1

Avinash Lemaire Avinash.persaud@sickkids.ca SickKids Research Institute Cell and Systems Biology Toronto Canada -

Co-author 2

Shaohu Sheng shaohu@pitt.edu University of Pittsburgh Medicine Pittsburgh United States -

Co-author 3

George Kefalas George.kefalas@alumni.utoronto.ca University of Toronto Biochemistry Toronto Canada -

Co-author 4

Krishna Ghandi Krishna.gandhi@sickkids.ca University of Toronto Biochemistry Toronto Canada -

Co-author 5

Patterson Larry larry.patterson@ufl.edu University of Florida Pediatrics Gainesville United States -

Co-author 6

JJ Zaritsky jzaritsky@phoenixchildrens.com Phoenix Children's Pediatrics Phoenix United States -

Co-author 7

Mohammed Almannai almannaimo@mngha.med.sa King Saud bin Abdulaziz University for Health Sciences Medicine Riyadh Saudi Arabia -

Co-author 8

Abdullah Al-Zulfa zulfaha@mngha.med.sa King Saud bin Abdulaziz University for Health Sciences Medicine Riyadh Saudi Arabia -

Co-author 9

Bader Alhaddad balhaddad@liferaomics.com.sa Lifera Omics N/A Riyadh Saudi Arabia -

Co-author 10

Shahd Al Awaji alawajish@mngha.med.sa King Abdullah Specialized Children Hospital Genetics and Precision Medicine Riyadh Saudi Arabia -

Co-author 11

Khadijah Bakur kbakur@liferaomics.com.sa Lifera Omics N/A Riyadh Saudi Arabia -

Co-author 12

Peter Snyder peter-snyder@uiowa.edu University of Iowa Medicine Iowa City United States -

Co-author 13

Tom Kleyman kleyman@pitt.edu University of Pittsburgh Medicine Pittsburgh United States -

Co-author 14

Mathieu Lemaire mathieu.lemaire@sickkids.ca Univeristy of Toronto Pediatrics Toronto Canada *

Co-author 15

Daniela Rotin drotin@sickkids.ca SickKids Research Institute Cell and Systems Biology Toronto Canada -

Introduction

Liddle Syndrome (LS) is an autosomal dominant form of hypertension caused by variants in the amiloride-sensitive Epithelial Na+ Channel (ENaC) that impair binding to its suppressor, the ubiquitin ligase NEDD4L. This stabilizes ENaC at the cell-surface, resulting in increased renal Na+ and fluid reabsorption and amiloride-sensitive hypertension. However, there are LS patients without ENaC variants and with unknown causes.

Methods

Next generation sequencing identified NEDD4L variants in patients with normal ENaC genes. We then analyzed ENaC cell-surface ubiquitination, stability and function by these identified NEDD4L variants.

Results

We describe two unrelated patients with LS-like disease with normal ENaC genes, but with pathogenic NEDD4L genotypes: one is a compound heterozygote (an early frameshift [GATTdel] and a missense [p.Y716D] in the catalytic HECT domain), and the other harbors homozygous nonsense variant [p.R563ter] upstream of the HECT domain. We demonstrate that all three variants impair NEDD4L enzymatic activity, leading to ENaC cell-surface retention and increased Na+ transport. In accord, amiloride treatment normalized blood-pressure in these patients. These data implicate NEDD4L as the cause of their LS-like disease. Uniquely, these patients also exhibit partial nephrogenic-diabetes-insipidus (NDI) and sensorineuronal hearing loss (SNHL), pathologies also described in existing Nedd4l knockout mice. On that basis, we propose naming this new disease, Liddle-NDI-Deafness (NEDD4L-LiNDID).

Conclusion

NEDD4L should be added to genetic panels for hypertension, NDI and SNHL, and NEDD4L-LiNDID should be suspected in patients with unexplained LS, NDI or SNHL. LiNDID patients will rapidly benefit from treatment with amiloride, an effective, cheap, and widely available life-saving drug.

Note: An earlier version of this work, presenting only one affected patient and less functional work, was presented at ASN meeting in 2023.

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