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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Polyhistidine tract expansions in HOXA1 result in intranuclear aggregation and increased cell death.

HOXA1 gene is part of a cluster of homeotic selector genes that regulates the anteroposterior patterning of mammals during embryonic development. HOXA1 encodes two alternatively spliced mRNAs with two isoforms, A and B, the former contains the homeodomain and expressed in early embryonic development. HOXA1 contains a string of 10 histidine repeats. However, individuals heterozygous for 7, 9, 11, and 12 histidine repeat variants were present among the Japanese population, notably in some autism cases. To determine the biological implications of the different polyhistidine repeat lengths, we expressed these variants in COS-7 and a human neuroblastoma cell line (SK-N-SH). Expression of expanded variants of HOXA1 isoform A, containing 11 and 12 polyhistidine, resulted in early and great degree of protein aggregation in the nucleus. This aggregation resulted in accelerated cell death in cells expressing 11 and 12 expanded variants compared to those transfected with 7 and 10 polyhistidine variants. Furthermore, we showed that these aggregates were ubiquitinated and were inhibited by a histidine-modifying compound, DEPC. These data suggest that HOXA1 protein with polyhistidine tract expansions misfold, aggregate, and have a toxic effect on cell.[1]


  1. Polyhistidine tract expansions in HOXA1 result in intranuclear aggregation and increased cell death. Paraguison, R.C., Higaki, K., Sakamoto, Y., Hashimoto, O., Miyake, N., Matsumoto, H., Yamamoto, K., Sasaki, T., Kato, N., Nanba, E. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
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