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Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder

Molecular Psychiatry volume 6, pages 387–395 (2001)Cite this article

Abstract

Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2, a chromosomal region that has been linked to BPD in a subset of families in several studies. Synaptojanin 1 is an inositol 5-phosphatase that has an important role in synaptic vesicle endocytosis. Mutation screening of 32 exons, intron–exon junctions, and 839 bases of 5′-flanking DNA resulted in the identification of 11 mutations of which four were very common and seven were very rare. Of the 11 mutations identified, several may have functional significance including two coding variants, two that may affect the binding of a transcription factor, and two that involve known splicing regulatory domains. Five bipolar patients out of 149 analyzed were found who have one of the four rare variants that were most likely to have functional significance compared with 0/148 controls. The allele frequencies for three of the four common variants were very similar in bipolar patients and controls. A slight difference in allele frequency was found for an interesting mutation we detected in intron 12 in which two non-adjacent thymidine residues are deleted in a poly-AT tract located near the exon 12 splice donor site (χ2?=?2.45, P?=?0.12, 2-tailed). Although we failed to unequivocally identify a specific SYNJ1 allele that could be responsible for putative chromosome 21q22-linked BPD, several interesting variants were found to be increased in bipolar subjects and should be further investigated.

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Acknowledgements

Some DNA samples were obtained from the Coriell Institute in conjunction with The National Institutes of Mental Health Bipolar Genetics Initiative, a multi-site study performed by four independent research teams in collaboration with extramural staff from the National Institute Mental Health (NIMH). The four Principal Investigators and Co-Investigators from the four sites are: Indiana University, Indianapolis, IN U01 MH46282, John Nurnberger, MD, PhD, Marvin Miller, MD, and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280, Theodore Reich, MD, Allison Goate, PhD, and John Rice, PhD; Johns Hopkins University, Baltimore MD U01 MH46274, J Raymond DePaulo, Jr, MD, Sylvia Simpson, MD, MPH, and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, MD, Diane Kazuba, BA, and Elizabeth Maxwell, MSW.

TS is supported by the American Psychiatric Association, Program for Minority Research Training in Psychiatry, and by a Young Investigator Award from NARSAD. HML is a recipient of a NARSAD Independent Investigator Award. DFP is a recipient of a NARSAD Independent Investigator Award.

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  1. Department of Psychiatry, Division of Psychiatry Research, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    T Saito, F Guan, D F Papolos, S Lau, M Klein, C S J Fann & H M Lachman

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  1. T Saito
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Correspondence to H M Lachman.

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Saito, T., Guan, F., Papolos, D. et al. Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder. Mol Psychiatry 6, 387–395 (2001). https://doi.org/10.1038/sj.mp.4000871

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