Biallelic < i > HEPHL1 < /i > variants impair ferroxidase activity and cause an abnormal hair phenotype

by Prashant Sharma, Marie Reichert, Yan Lu, Thomas C. Markello, David R. Adams, Peter J. Steinbach, Brie K. Fuqua, Xenia Parisi, Stephen G. Kaler, Christopher D. Vulpe, Gregory J. Anderson, William A. Gahl, May Christine V. Malicdan

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-characterize d 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 inHEPHL1 (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...

Source: PLoS Genetics - May 23, 2019 Category: Genetics & Stem Cells Authors: Prashant Sharma Source Type: research