title: Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B.
abstract: The increased incidence of minor physical anomalies (MPAs) in schizophrenia is the fundamental basis for the neurodevelopmental hypothesis of schizophrenia etiology. Ocular misalignment, or strabismus, falls into the category of MPAs, but this phenotype has not been assessed in schizophrenia. This study reveals that a subtype of strabismus, constant exotropia, displays marked association with schizophrenia (P=0.00000000906). To assess the genetic mechanisms, we examined the transcription factor genes ARIX (recently identified as a causative gene for syndromic strabismus) and its paralogue, PMX2B. We identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PMX2B, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia (P=0.029). The polymorphisms were also associated with overall schizophrenia (P=0.012) and more specifically with schizophrenia manifesting strabismus (P=0.004). These results suggest a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. This study also highlights the unique nature of the polyalanine length variations found in PMX2B. In contrast with other transcription factor genes, the variations in PMX2B show a high prevalence, with deletions being more common than insertions. Additionally, the polymorphisms are of ancient origin and stably transmitted, with mild phenotypic effects. In summary, our study lends further support to the disruption of neurodevelopment in the etiology of schizophrenia, by demonstrating the association of a specific MPA, in this case, constant exotropia with schizophrenia, along with molecular variations in a possible causative gene.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshitsugu
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ebihara
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Hisako
authors.initials: H
authors.lastname: Ohba
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukasawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Minabe
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yoshimoto
authors.initials: Y
authors.lastname: Sekine
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Takei
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Suzuki
authors.forename: Masanari
authors.initials: M
authors.lastname: Itokawa
authors.forename: Joanne M A
authors.initials: JM
authors.lastname: Meerabux
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama-Shigeno
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Tomaru
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Shimizu
authors.forename: Eiji
authors.initials: E
authors.lastname: Hattori
authors.forename: Norio
authors.initials: N
authors.lastname: Mori
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D001483:Base Sequence; D016000:Cluster Analysis; D017931:DNA Primers; D005099:Exotropia / Q000150:complications*; D040461:Gene Components; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008156:Luciferases; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000235:genetics; D011110:Polymorphism, Genetic; D012559:Schizophrenia / Q000150:complications*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; C109220:NBPhox protein; C491061:PHOX2A protein, human; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine; D008156:Luciferases