ArticlePLoS genetics2019
Biallelic HEPHL1 variants impair ferroxidase activity and cause an abnormal hair phenotype.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
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- Biallelic germline DDX41 variants in a patient with bone dysplasia, ichthyosis, and dysmorphic features.Human genetics · 2024Article
- Iron Metabolism of the Skin: Recycling versus Release.Metabolites · 2023Review
- Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis.American journal of human genetics · 2023Article
- The biology of mammalian multi-copper ferroxidases.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2023Review
- Microbiome-transcriptome analysis reveals that dietary supplementation with macleaya cordata extract alters multiple immune pathways with minimal impact on microbial structure.Frontiers in cellular and infection microbiology · 2023Article
- Genome-wide detection of RNA editing events during the hair follicles cycle of Tianzhu white yak.BMC genomics · 2022Article
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- Uterus-specific transcriptional regulation underlies eggshell pigment production in Japanese quail.PloS one · 2022Article
- NovelHypertension (Dallas, Tex. : 1979) · 2022Article
- Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver.Antioxidants (Basel, Switzerland) · 2021Review
- Pili Torti: A Feature of Numerous Congenital and Acquired Conditions.Journal of clinical medicine · 2021Review
- Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection.Journal of clinical medicine · 2021Article
- A Nonsense Variant in Hephaestin Like 1 (Genes · 2021Article
- Review
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Maintenance of the correct redox status of iron is functionally important for critical biological processes. Multicopper ferroxidases play an important role in oxidizing ferrous iron, released from the cells, into ferric iron, which is subsequently distributed by transferrin. Two well-characterized ferroxidases, ceruloplasmin (CP) and hephaestin (HEPH) facilitate this reaction in different tissues. Recently, a novel ferroxidase, Hephaestin like 1 (HEPHL1), also known as zyklopen, was identified. Here we report a child with compound heterozygous mutations in HEPHL1 (NM_001098672) who presented with abnormal hair (pili torti and trichorrhexis nodosa) and cognitive dysfunction. The maternal missense mutation affected mRNA splicing, leading to skipping of exon 5 and causing an in-frame deletion of 85 amino acids (c.809_1063del; p.Leu271_ala355del). The paternal mutation (c.3176T>C; p.Met1059Thr) changed a highly conserved methionine that is part of a typical type I copper binding site in HEPHL1. We demonstrated that HEPHL1 has ferroxidase activity and that the patient's two mutations exhibited loss of this ferroxidase activity. Consistent with these findings, the patient's fibroblasts accumulated intracellular iron and exhibited reduced activity of the copper-dependent enzyme, lysyl oxidase. These results suggest that the patient's biallelic variants are loss-of-function mutations. Hence, we generated a Hephl1 knockout mouse model that was viable and had curly whiskers, consistent with the hair phenotype in our patient. These results enhance our understanding of the function of HEPHL1 and implicate altered ferroxidase activity in hair growth and hair disorders.
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