LONP1 Variants Are Associated With Clinically Diverse Phenotypes

Randee E Young¹, Lu Qiao^{2

3}, Rebecca Hernan¹, David A Sweetser⁴, Jessica L Waxler¹, Daryl A Scott⁵, Tiana M Scott⁵, Seema R Lalani⁵, Mahshid S Azamian⁵, Jill A Rosenfeld⁵, Bret Bostwick⁵, Lindsay C Burrage^{5

6}; Undiagnosed Diseases Network; Lance H Rodan⁷, Bianca E Russell⁸, Marina Dutra-Clarke⁸, Michael Kruer^{9

10}, Somayeh Bakhtiarim^{9

10}, Hossein Darvish¹¹, David J Amor¹², Shamima Rahman¹³, Karen Stals¹⁴, Lisa Bradley¹⁵, Susan Byrne¹⁵, Leandra K Tolusso¹⁶, Beatrix Wong¹⁶, Laura Benedict¹⁷, Kimberly Wallis¹⁷, Kestutis Micke¹⁸, Cindy Colson¹⁹, Thomas Smol¹⁹, Sabrina V Southwick²⁰, Kristen A Miller²⁰, Michelle L Kush²¹, Odelia Chorin²², Annick Rothschild²², Wei Wang²³, Yufeng Shen^{3

24

25}, Wendy K Chung¹

Affiliations

¹ Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.
³ Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA.
⁴ Division of Medical Genetics and Metabolism, Department of Pediatrics; and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁶ Texas Children's Hospital, Houston, Texas, USA.
⁷ Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Department of Human Genetics, Division of Clinical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
⁹ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA.
¹⁰ Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
¹¹ Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
¹² Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia.
¹³ Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Department, Great Ormond Street Hospital for Children, London, UK.
¹⁴ Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
¹⁵ Department of Clinical Genetics and Department of Neurology, Children's Health Ireland (CHI) at Crumlin, Dublin, Ireland.
¹⁶ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹⁷ Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁸ Colorado Fetal Care Center, Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁹ Univ. Lille, CHU Lille, ULR7364-RADEME-Maladies RAres du DEveloppement Embryonnaire et du Métabolisme, CRMR Anomalies du Développement et Syndromes Malformatifs, Lille, France.
²⁰ Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, Maryland, USA.
²¹ Center for Fetal Therapy, Department of Gynecology & Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA.
²² Institute of Rare Diseases, Edmond and Lily Safra Hospital for Children, the Danek Gertner Institute of Genetics, Sheba Medical Center, Ramat Gan, Israel.
²³ GeneDx, LLC, Gaithersburg, Maryland, USA.
²⁴ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
²⁵ JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, New York, USA.

PMID: 40931319
DOI: 10.1111/cge.70057

LONP1 Variants Are Associated With Clinically Diverse Phenotypes

Randee E Young et al. Clin Genet. 2025.

. 2025 Sep 10.

doi: 10.1111/cge.70057. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.
³ Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA.
⁴ Division of Medical Genetics and Metabolism, Department of Pediatrics; and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁶ Texas Children's Hospital, Houston, Texas, USA.
⁷ Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Department of Human Genetics, Division of Clinical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
⁹ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, Arizona, USA.
¹⁰ Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA.
¹¹ Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
¹² Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia.
¹³ Mitochondrial Research Group, UCL Great Ormond Street Institute of Child Health, and Metabolic Department, Great Ormond Street Hospital for Children, London, UK.
¹⁴ Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
¹⁵ Department of Clinical Genetics and Department of Neurology, Children's Health Ireland (CHI) at Crumlin, Dublin, Ireland.
¹⁶ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹⁷ Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁸ Colorado Fetal Care Center, Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁹ Univ. Lille, CHU Lille, ULR7364-RADEME-Maladies RAres du DEveloppement Embryonnaire et du Métabolisme, CRMR Anomalies du Développement et Syndromes Malformatifs, Lille, France.
²⁰ Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins Hospital, Baltimore, Maryland, USA.
²¹ Center for Fetal Therapy, Department of Gynecology & Obstetrics, Johns Hopkins University, Baltimore, Maryland, USA.
²² Institute of Rare Diseases, Edmond and Lily Safra Hospital for Children, the Danek Gertner Institute of Genetics, Sheba Medical Center, Ramat Gan, Israel.
²³ GeneDx, LLC, Gaithersburg, Maryland, USA.
²⁴ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
²⁵ JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, New York, USA.

PMID: 40931319
DOI: 10.1111/cge.70057

Abstract

LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.

Keywords: CODAS; LONP1; congenital diaphragmatic hernia; mitochondrial encephalopathy; neurodevelopmental disorder.

PubMed Disclaimer

References

1. D. A. Bota and K. J. A. Davies, “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon‐Related Diseases and Disorders,” Free Radical Biology & Medicine 100 (2016): 188–198.
1. D. A. Bota and K. J. A. Davies, “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP‐Stimulated Mechanism,” Nature Cell Biology 4 (2002): 674–680.
1. J. Song, J. M. Herrmann, and T. Becker, “Quality Control of the Mitochondrial Proteome,” Nature Reviews Molecular Cell Biology 22 (2021): 54–70, https://doi.org/10.1038/s41580‐020‐00300‐2.
1. C.‐S. Shin, S. Meng, S. D. Garbis, et al., “LONP1 and mtHSP70 Cooperate to Promote Mitochondrial Protein Folding,” Nature Communications 12 (2021): 265.
1. B. Lu, S. Yadav, P. G. Shah, et al., “Roles for the Human ATP‐Dependent Lon Protease in Mitochondrial DNA Maintenance,” Journal of Biological Chemistry 282 (2007): 17363–17374.

Grants and funding

LinkOut - more resources

Full Text Sources
- Wiley

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

LONP1 Variants Are Associated With Clinically Diverse Phenotypes

Affiliations

LONP1 Variants Are Associated With Clinically Diverse Phenotypes

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Full Text Sources