title: EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts with SIX3 both physically and functionally.
abstract: Holoprosencephaly (HPE) is the most common congenital malformation of the developing human forebrain, in which the two cerebral hemispheres fail to separate to various degrees. Although pathological mutations have been identified in up to nine genes, a number of other genes as well as environmental factors are likely to be involved in HPE. Here, we describe a case with the middle interhemispheric variant, a milder variant of HPE, carrying a deletion of approximately 10.4 Mb at 6q22.31-q23.2, which includes the EYA4 gene. EYA4 is one of four vertebrate orthologs of the Drosophila melanogaster gene, eyes absent. EYA4 was co-immunoprecipitated with SIX3, the product of one of the known HPE genes. Moreover, the EYA4 protein was observed to be recruited to the nucleus by the nuclear protein SIX3 under a confocal microscope. EYA4 is a transcriptional coactivator, and was shown to cooperate with transcription factor SIX3 by reporter gene assays. These results demonstrate physical and functional association between EYA4 and SIX3, suggesting that EYA4 is a novel candidate gene of HPE, whose haploinsufficiency leads to HPE through the compromised function of SIX3.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Science, Kitasato University, Sagamihara 228-8555 Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Abe
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Igarashi
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagao
authors.forename: Masao
authors.initials: M
authors.lastname: Yamada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyashita
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000097607:Homeobox Protein SIX3
chemical_list: D017931:DNA Primers; D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D000097607:Homeobox Protein SIX3; C117736:EYA4 protein, human