Autosomal dominant Zellweger spectrum disorder caused by de novo variants in PEX14 gene.

Autor:	Waterham HR; Amsterdam UMC - AMC, Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands; United for Metabolic Diseases, The Netherlands. Electronic address: h.r.waterham@amsterdamumc.nl., Koster J; Amsterdam UMC - AMC, Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands., Ebberink MS; Amsterdam UMC - AMC, Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands., Ješina P; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague 2, Czech Republic., Zeman J; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague 2, Czech Republic., Nosková L; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague 2, Czech Republic., Kmoch S; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague 2, Czech Republic., Devic P; Centre Hospitalier Universitaire de Lyon, CHU Lyon·U 301, Hopital Neurologique, Bron, France., Cheillan D; Service Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Groupement Hospitalier Est - Hospices Civils de Lyon, Bron Cedex, France., Wanders RJA; Amsterdam UMC - AMC, Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands; Amsterdam Reproduction & Development, Amsterdam, The Netherlands; United for Metabolic Diseases, The Netherlands., Ferdinandusse S; Amsterdam UMC - AMC, Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2023 Nov; Vol. 25 (11), pp. 100944. Date of Electronic Publication: 2023 Jul 23.
DOI:	10.1016/j.gim.2023.100944
Abstrakt:	Purpose: Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD. Methods: We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies. Results: We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts. Conclusion: Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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