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Human Molecular Genetics Advance Access originally published online on January 6, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 5 551-561
DOI: 10.1093/hmg/ddh047

Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B

Tomoko Toyota1,2, Kiyoshi Yoshitsugu1,2, Mitsuru Ebihara1, Kazuo Yamada1, Hisako Ohba1, Masayuki Fukasawa1,2, Yoshio Minabe1,3, Kazuhiko Nakamura1,3, Yoshimoto Sekine3, Noriyoshi Takei3, Katsuaki Suzuki3, Masanari Itokawa1, Joanne M.A. Meerabux1, Yoshimi Iwayama-Shigeno1, Yoshiro Tomaru4, Hiromitsu Shimizu5, Eiji Hattori1, Norio Mori3 and Takeo Yoshikawa1,*

1Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, 2Department of Neuropsychiatry, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, 3Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan, 4Yamada Hospital, Chofu, Tokyo 182-0005, Japan and 5Hokushin General Hospital, Nakano, Nagano 383-8505, Japan

Received November 10, 2003; Accepted December 17, 2003

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.

* To whom correspondence should be addressed at: Laboratory for Molecular Psychiatry, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Tel: +8 1484675968; Fax: +8 1484675916; Email: takeo{at}brain.riken.go.jp


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