title: Polyhistidine tract expansions in HOXA1 result in intranuclear aggregation and increased cell death.
abstract: 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.
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors.forename: Rubigilda C
authors.initials: RC
authors.lastname: Paraguison
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Ohiko
authors.initials: O
authors.lastname: Hashimoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sasaki
authors.forename: Nobumasa
authors.initials: N
authors.lastname: Kato
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004047:Diethyl Pyrocarbonate / Q000494:pharmacology; D006639:Histidine / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D000099261:Homeobox A1 Protein
chemical_list: D004047:Diethyl Pyrocarbonate; D006639:Histidine; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; D025801:Ubiquitin; D000099261:Homeobox A1 Protein; C033223:polyhistidine