TY - JOUR
T1 - Autosomal dominant Zellweger spectrum disorder caused by de novo variants in PEX14 gene
AU - Waterham, Hans R.
AU - Koster, Janet
AU - Ebberink, Merel S.
AU - Ješina, Pavel
AU - Zeman, Jiri
AU - Nosková, Lenka
AU - Kmoch, Stanislav
AU - Devic, Perrine
AU - Cheillan, David
AU - Wanders, Ronald J. A.
AU - Ferdinandusse, Sacha
N1 - Funding Information: J.Z. and S.K. were supported by grant NV19-07-00136 from the Ministry of Health of the Czech Republic and acknowledge The National Center for Medical Genomics (LM2018132) for instrumental and methodologic support with the exome sequencing analyses. P.J. was supported by the institutional grant RVO VFN64165 from the Ministry of Health of the Czech Republic. Funding Information: This work was supported in part by E-Rare-3 Joint Translational Call PERescue (2015) supported by The Netherlands Organization for Health Research and Development (ZonMW; H.R.W. and J.K.). Funding Information: We thank Petra Mooijer and Conny Dekker for technical assistance and acknowledge Gaby Dodt, Marc Fransen, and Denis Crane for provision of antibodies. This work was supported in part by E-Rare-3 Joint Translational Call PERescue (2015) supported by The Netherlands Organization for Health Research and Development (ZonMW; H.R.W. and J.K.). J.Z. and S.K. were supported by grant NV19-07-00136 from the Ministry of Health of the Czech Republic and acknowledge The National Center for Medical Genomics (LM2018132) for instrumental and methodologic support with the exome sequencing analyses. P.J. was supported by the institutional grant RVO VFN64165 from the Ministry of Health of the Czech Republic. Conceptualization: H.R.W. J.K. S.F.; Formal Analysis: H.R.W. J.K. S.F.; Investigation: J.K. M.S.E. J.Z. L.N. S.K. P.D. D.C. S.F.; Methodology: H.R.W. J.K.; Project administration: H.R.W.; Resources: P.J. J.Z. S.K. P.D. D.C.; Supervision: H.R.W.; Visualization: H.R.W. J.K.; Writing – original draft: H.R.W. J.K.; Writing – review & editing: H.R.W. J.K. M.S.E. R.J.A.W. S.F. The study on patient 1 was approved by the Ethics committee of the General University Hospital in Prague and was conducted in agreement with the Declaration of Helsinki and institutional guidelines. Written informed consent for molecular analyses was obtained from the patient and his mother. The study on patient 2 was conducted in agreement with the Declaration of Helsinki and institutional guidelines. A specific written informed consent for molecular analyses was obtained from the patient. The Medical Ethics Review Committee of the Amsterdam UMC, where most of the laboratory diagnostics and all functional studies have been performed, has indicated that functional follow-up studies do not require their official approval, because these studies are not considered ‘research with or involving human subjects’ and thus the ‘Medical Research Involving Human Subjects Act’ (WMO) does not apply. Publisher Copyright: © 2023 The Authors
PY - 2023/11/1
Y1 - 2023/11/1
N2 - 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.
AB - 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.
KW - Autophagy
KW - Metabolic disorder
KW - Peroxisomal disorder
KW - Peroxisome
KW - Peroxisome biogenesis
UR - http://www.scopus.com/inward/record.url?scp=85168337755&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.gim.2023.100944
DO - https://doi.org/10.1016/j.gim.2023.100944
M3 - Article
C2 - 37493040
SN - 1098-3600
VL - 25
JO - Genetics in medicine
JF - Genetics in medicine
IS - 11
M1 - 100944
ER -