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

Autor:	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., Park YN; Department of Human Genetics, University of Michigan, Ann Arbor, MI., Lenk GM; Department of Human Genetics, University of Michigan, Ann Arbor, MI., Severino M; Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy., 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., Denecke J; University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany., Hempel M; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Lessel D; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Kortüm F; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., 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., de Marco P; UOC Genetica Medica, IRCCS G. Gaslini, Genoa, Italy., Guerrisi S; UOC Genetica Medica, IRCCS G. Gaslini, Genoa, Italy., Torella A; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., Nigro V; Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy., 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., 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., 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., Freson K; Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium., Piatelli G; Department of Neurosurgery, Gaslini Children's Hospital, Genoa, Italy., Capra V; Genomics and Clinical Genetics, IRCCS Instituto G. Gaslini, Genoa, Italy., Kitzman JO; Department of Human Genetics, University of Michigan, Ann Arbor, MI., Meisler MH; Department of Human Genetics, University of Michigan, Ann Arbor, MI. Electronic address: meislerm@umich.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 May; Vol. 26 (5), pp. 101097. Date of Electronic Publication: 2024 Feb 05.
DOI:	10.1016/j.gim.2024.101097
Abstrakt:	Purpose: 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 -/- cells. Methods: 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. Results: Overexpression of SLC12A9, a solute co-transporter, corrected lysosomal swelling in FIG4 -/- cells. SLC12A9 (NP_064631.2) colocalized with LAMP2 at the lysosome membrane. Biallelic variants of SLC12A9 were identified in 3 unrelated probands with neurodevelopmental disorders. Common features included intellectual disability, skeletal and brain structural abnormalities, congenital heart defects, and hypopigmented hair. Patient 1 was homozygous for nonsense variant p.(Arg615∗), patient 2 was compound heterozygous for p.(Ser109Lysfs∗20) and a large deletion, and proband 3 was compound heterozygous for p.(Glu290Glyfs∗36) and p.(Asn552Lys). Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wild-type SLC12A9 cDNA. Patient variant p.(Asn552Lys) failed to correct the lysosomal defect. Conclusion: Impaired function of SLC12A9 results in enlarged lysosomes and a recessive disorder with a recognizable neurodevelopmental phenotype. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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