Title : Biallelic
HEPHL1 variants impair
ferroxidase activity and cause an abnormal hair phenotype
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