The protein encoded by the HFE gene is a non-classical HLA class I-like protein which contains a signal sequence, peptide-binding extracellular domains, a trans-membran region and a small cytoplasmic portion. Within the α-2 and α-3 extracellular domains, are the four cysteine residues that form disulphide bridges representing one of the most conserved structural features of class I molecules. HFE interacts with β2 m, and this association enables efficient transport of HFE to the cell surface where it interacts with transferin receptor 1. C282Y mutation disrupts the disulphide bridges in the extracellular domains of the HFE protein, thereby preventing the association of HFE with β2 m and transferin receptor 1. The lack of HFE interaction with transferin receptor 1 increases affinity of transferin receptor 1 for the transferin-bound iron, thereby modulating iron absorption. In contrast to the C282Y mutation, mutant H63D HFE formed stable complexes with tranferin receptor 1 being in line with the clinical data that H63D HFE mutationsmmarginally affect iron absorption and rarely lead to hemochromatosis.
Iron-overload disoreders owing to genetic mis-regulation of iron aquisition are referred to as hemochromatosis. The most prevalent genetic iron-overload disorders in Caucasian is caused by mutation in the HFE gene, an atypical HLA class I molecule. The HFE gene was first identified in 1996 as an major histocompatibility complex class I-like gene in which homozygosity for a missense mutation that results in cystein-to-tyrosyne substitution at amino acid 282 of human HFE protein (C282Y) was found in vast majority of patients with hemochromatosis.
Among autoimmune disease, narcolepsy is uniquely positioned to demonstrate molecular mimicry in humans. First, narcolepsy occurs nearly exclusively in individuals with DQB1*0602. Second, a specific association with the T receptor cell-α locus also confers an increased risk, indicating a crucial role for specific J segments of T cell receptor-α in the “immunological synapse” of narcolepsy.
While nearly all narcoleptic patients express DQB1*0602, expression of DQB1*0602 is not limited to narcoleptic individuals between 12% and 38% of the general population are carries of this allele. In contrast, the closely related DQB1*0601 allele, which differs at only nine residues, protects against developing narcolepsy, suggesting that peptide-binding differences between these two alleles determine whether they predispose to or protect against narcolepsy. The significant association with DQB1*0602 strongly suggest an interaction between a specific T cell receptors subtype leading to the destruction of hypocretin-producing neurons. An autoimmune basis for the hypocretin cell loss in narcolepsy has long been suspected due to its strong genetic association with selected HLA alleles. HLA encodes multiple subtypes of HLA class I and II proteins that present foreign peptides to T cells during infections, thereby triggering immune responses via T cell receptors activation. In autoimmunity, self-peptides are believed to be mistakenly perceived as foreign, thus leading to tissue destruction, which often occurs in context of specific HLA alleles.
To act, hypocretins must bind to receptors, one of which is rendered non-functional by a mutation carried by patients with narcolepsy. The mutation apparently arose in a common ancestor of these patients, in the HCRTR2 gene located in the vicinity of the HLA-DQB1*0602 and DQA1*0102 alleles. As the mutation occured relatively recently, there has not been enough time for it to be separated from the two HLA-DQ alleles by crossing over in the patients with the most severe cases of narcolepsy. The three genes therefore appear together at frequencies higher than would be expected from random combination of their frequencies in the population, a situation referred as linkage disequilibrium
Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep patterns. This disease is secondary to the specific loss of hypothalamic hypocretin (orexin)-producing neurons in the lateral hypothalamus.
Abnormalities of genes linked to the HLA
A large group of dieseases involved genes in the HLA region that are linked to (or associated with) specific class I and class II alleles or combinations of alleles (haplotypes). In some of these disease, the responsible genes are unrelated to the class I and class II genes (eg Narcolepcy), but in other diseases, the class I, II and II genes are involved