Structure and polymorphism of the human gene for the interferon-induced p78 protein (MX1): evidence of association with alopecia areata in the Down syndrome region

Abstract

Alopecia areata (AA) is a chronic inflammatory disease characterised by patchy hair loss with T cell infiltration of hair follicles. AA occurs in approximately 0.1% of the general population, but this is increased to 9% in Down syndrome (DS). DS is associated with an additional copy (full or partial) of chromosome 21, and the DS region may potentially include genes involved in the pathogenesis of AA. MX1 is the gene encoding the interferon-induced p78 protein (MxA). MxA protein confers resistance to influenza viruses, and we have previously shown that MxA protein is strongly expressed in lesional anagen hair bulbs from patients with AA but not in normal follicles. We therefore studied the possible involvement of MX1 in the pathogenesis of AA. To establish markers in the MX1 region which could be screened by PCR-based methods, we defined the human MX1 exon/intron organisation and screened the exons and the introns by conformation-sensitive gel electrophoresis. We found that the MX1 gene contains 17 exons extending over 33 kb. The size and sequence of the region from exon 6 to exon 16 are highly conserved between human and mouse. Screening of 4747 bp within the MX1 gene revealed four single nucleotide polymorphisms in intron 6. These polymorphisms are concentrated within 147 bp and show strong linkage disequilibrium. In a case-control association study for the MX1 (+9959) polymorphism in 165 AA patients and 510 controls we found a significant association of this marker with AA (odds ratio 1.79, 95% CI 1.21-2.66, chi2 = 8.464, P = 0.0036). The risk of disease was greater for patchy AA (mild disease) and with early age at onset (odds ratio 2.34, 95% CI 1.24-4.43, P = 0.0072), providing new evidence of genetic heterogeneity in AA. Our demonstration of genetic association between the MX1 gene and disease supports the hypothesis that this is a new candidate gene in AA.

Role of Nucleotide Binding and GTPase Domain Dimerization in Dynamin-like Myxovirus Resistance Protein A for GTPase Activation and Antiviral Activity

“…The human MX1 gene is highly conserved and only a few single nucleotide polymorphisms are described in the human population (57). However, a recent study analyzing variations in the MxA genes of 267 healthy individuals identified two rare nucleotide changes that result in amino acid exchanges at positions 255 and 268 (50).…”

Alopecia areata: pathogenesis and potential for therapy

“…Tumour necrosis factor α (TNF-α) gene polymorphism, or adjacent genes in the HLA region, might also influence AA susceptibility (Refs 86, 87). More-recent gene association studies have identified specific polymorphisms in the genes encoding MX1, AIRE and NOTCH4 ( Refs 88,89,90).…”

Inhibition of Tumor Cell Motility by the Interferon-inducible GTPase MxA

“…There was no sequence alteration in the tripartite GTPase domain or the self-assembly domains. The difference observed may be the result of human sequence polymorphisms (24). MxA expression has only been reported following viral infection or treatment with IFNs (3-5).…”