Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy
Joseph T. Shieh,
Jesus A. Tintos-Hernandez,
Chaya N. Murali,
Monica Penon-Portmann,
Marco Flores-Mendez,
Adrian Santana,
Joshua A. Bulos,
Kang Du,
Lucie Dupuis,
Nadirah Damseh,
Roberto Mendoza-Londoño,
Camilla Berera,
Julieann C. Lee,
Joanna J. Phillips,
César A.P.F. Alves,
Ivan J. Dmochowski,
Xilma R. Ortiz-González
Affiliations
Joseph T. Shieh
Institute for Human Genetics and Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Corresponding author
Jesus A. Tintos-Hernandez
Division of Neurology and Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Chaya N. Murali
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Monica Penon-Portmann
Institute for Human Genetics and Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA
Marco Flores-Mendez
Division of Neurology and Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Adrian Santana
Division of Neurology and Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Joshua A. Bulos
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
Kang Du
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
Lucie Dupuis
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
Nadirah Damseh
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
Roberto Mendoza-Londoño
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
Camilla Berera
Institute for Human Genetics and Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA
Julieann C. Lee
Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA
Joanna J. Phillips
Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
César A.P.F. Alves
Division of Neuroradiology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Ivan J. Dmochowski
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
Xilma R. Ortiz-González
Division of Neurology and Center for Mitochondrial and Epigenomic Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Epilepsy Neurogenetics Initiative (ENGIN), The Children’s Hospital of Philadelphia and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin’s E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.
