Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder.

Co-transporter Lysosome Neurodevelopmental disorder Osmoregulation SLC12A9

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
05 Feb 2024
Historique:
received: 02 08 2023
revised: 31 01 2024
accepted: 01 02 2024
pubmed: 9 2 2024
medline: 9 2 2024
entrez: 9 2 2024
Statut: aheadofprint

Résumé

Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4 The CRISPR-a gene activation screen utilized sgRNAs from the promoters of protein-coding genes. Fluorescence-activated cell sorting separated cells with correction of the enlarged lysosomes from uncorrected cells. Patient variants of SLC12A9 were identified by exome or genome sequencing and studied by segregation analysis and clinical characterization. Overexpression of SLC12A9, a solute co-transporter, corrected lysosomal swelling in FIG4 Impaired function of SLC12A9 results in enlarged lysosomes and a recessive disorder with a recognizable neurodevelopmental phenotype.

Identifiants

DOI: 10.1016/j.gim.2024.101097 PMID: 38334070
pubmed: 38334070
pii: S1098-3600(24)00030-3
doi: 10.1016/j.gim.2024.101097
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101097

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM024872
Pays : United States

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of Interest The authors declare no conflicts of interest.

Auteurs

Andrea Accogli (A)

Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre (MUHC), Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.

Young N Park (YN)

Department of Human Genetics, University of Michigan, Ann Arbor, MI.

Guy M Lenk (GM)

Department of Human Genetics, University of Michigan, Ann Arbor, MI.

Mariasavina Severino (M)

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Marcello Scala (M)

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università Degli Studi di Genova, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Jonas Denecke (J)

University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.

Maja Hempel (M)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Davor Lessel (D)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Fanny Kortüm (F)

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Vincenzo Salpietro (V)

Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, United Kingdom; Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100, L'Aquila, Italy.

Patrizia de Marco (P)

UOC Genetica Medica, IRCCS G. Gaslini, Genoa, Italy.

Sara Guerrisi (S)

UOC Genetica Medica, IRCCS G. Gaslini, Genoa, Italy.

Annalaura Torella (A)

Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Vincenzo Nigro (V)

Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Myriam Srour (M)

Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Pediatrics, Division of Pediatric Neurology, McGill University, Montreal, QC, Canada; McGill University Health Center (MUHC) Research Institute, Montreal, QC, Canada; Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

Ernest Turro (E)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Veerle Labarque (V)

Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium; Paediatric Hemato-Oncology, University Hospitals Leuven, Leuven, Belgium.

Kathleen Freson (K)

Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.

Gianluca Piatelli (G)

Department of Neurosurgery, Gaslini Children's Hospital, Genoa, Italy.

Valeria Capra (V)

Genomics and Clinical Genetics, IRCCS Instituto G. Gaslini, Genoa, Italy.

Jacob O Kitzman (JO)

Department of Human Genetics, University of Michigan, Ann Arbor, MI.

Miriam H Meisler (MH)

Department of Human Genetics, University of Michigan, Ann Arbor, MI. Electronic address: meislerm@umich.edu.

Classifications MeSH