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Down Syndrome Abstract
of the Month: Aug 2000

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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

Tazi-Ahnini R et al.
Hum Genet 2000 Jun;106(6):639-45

Division of Molecular and Genetic Medicine, University of Sheffield, Royal Hallamshire Hospital, UK.

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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 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). 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. The risk of disease was greater for patchy AA (mild disease) and with early age at onset, 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.

My comments:

This was a study of 165 adults with alopeica areata (AA), not a study of any patients with Down syndrome. But the conclusion that certain variations ("polymorphisms") of the MX1 gene, which is located on the 21st chromosome, have an impact on AA is significant to us. The authors speculate that to develop AA, the person must have two copies of the variation of this gene. This type of requirement means the variant gene producing AA is called "recessive." If you have three 21st chromosomes, that gives you one extra chance at having two of the variant genes, so that would explain why AA is more common in people with Down syndrome than in the general population.

I believe this is the closest we've come so far to identifying a feature of Down syndrome with a specific gene. The next step would be to examine the MX1 gene types in people with Down syndrome and AA.

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