A novel deletion in the FTL gene causes hereditary hyperferritinemia cataract syndrome (HHCS) by alteration of the transcription start site.

Hereditary hyperferritinemia cataract syndrome (HHCS) is characterized by distinctive cataracts and high serum ferritin in the absence of iron overload. It is caused by mutations in the iron response element (IRE) of the Ferritin Light Chain (FTL) gene. Here we investigate the genetics of HHCS in a three generation Australian kindred with typical HHCS ocular lens morphology and high ferritin levels. Initial sequencing of the IRE failed to detect any mutations. Sequencing of the entire gene including the promoter region revealed a novel 25 bp deletion upstream of the IRE abolishing the transcription start site. In lymphoblastoid cells, the deletion allele was transcribed from an alternate start site within the lower stem of the IRE and mutation carriers had high cellular L-ferritin levels. This novel deletion in the promoter encompassing the transcription start site of the FTL gene is responsible for HHCS in this kindred. The initial primers for amplifying the IRE similar to those used by other researchers failed to detect this mutation. Therefore the genomic region assessed in HHCS cases for diagnosis should be expanded to include mutations of this type.