Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene.
Iron availability regulates ferritin synthesis posttranscriptionally by the interaction between iron-regulatory proteins (IRPs) and an iron responsive element (IRE), a stem-loop sequence located on the 5' untranslated region of ferritin mRNA. IRPs recognize IREs as a sequence/structure motif, blocking ferritin translation. Recently, we and others independently described families with a combination of hyperferritinemia (serum L-ferritin > or = 1,000 microg/L, without iron overload) and congenital bilateral cataract, transmitted as an autosomal-dominant trait. The molecular basis were two distinct point mutations in the highly conserved CAGUG(X) hexaloop of L-ferritin IRE on chromosome 19. A new three-generation family with a similar phenotype and a unique genotype is here reported. DNA amplification by polymerase chain reaction and sequence analysis showed a 29-base pair deletion in the L-ferritin IRE, involving the whole 5' sequence essential to the base pairing of the IRE stem. This deletion is predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) appears as a new genetic disorder with a unique phenotype associated with at least four different mutations in the L-ferritin IRE. Hematologists should take into account HHCS in the differential diagnosis of unexplained hyperferritinemia.
Girelli
D
D
Institute of Medical Pathology, University of Verona, Italy.
Corrocher
R
R
Bisceglia
L
L
Olivieri
O
O
Zelante
L
L
Panozzo
G
G
Gasparini
P
P
D000328:Adult; D002386:Cataract / Q000097:blood / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19; D005260:Female; D005293:Ferritins / Q000097:blood / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013577:Syndrome
D005293:Ferritins; D007501:Iron