Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey.
OBJECTIVE
Though genetic factors play a major role in the pathophysiology of psychoses including bipolar disorder (BD) and schizophrenia, lack of well-established causative genetic mutations hampers their neurobiological studies. Darier's disease, an autosomal dominant skin disorder caused by mutations of ATP2A2 on chromosome 12q23-24.1, encoding sarco/endoplasmic reticulum calcium transporting ATPase 2 (SERCA2), reportedly cosegregates with BD. A recent genome-wide association study showed an association of schizophrenia with ATP2A2.


METHODS
We sequenced all coding regions of ATP2A2 in a newly identified patient with Darier's disease and BD. In addition, we performed a literature survey to examine whether likely gene disrupting (LGD) mutations are related to psychoses.


RESULTS
We identified a rare heterozygous mutation, c.1288-6A>G, at the 3' end of intron 10 in the patient. A minigene splicing assay showed that this mutation introduces a new splice site causing a frameshift and premature stop codon. A literature survey of case reports of patients with Darier's disease and psychoses revealed that the rate of LGD mutations causing frameshift, altered splicing, gain of stop codon, or loss of start codon was significantly higher among the mutations harbored by these cases (9 of 11) than that of ATP2A2 mutations for which comorbidity of psychosis was not reported (107 of 237, P = 0.026). The only non-LGD mutation (p.C560R) reported in patients with Darier's disease and BD caused decreased ATP2A2 protein expression.


CONCLUSIONS
These results suggest that psychoses in Darier's disease may be caused by a pleiotropic effect of loss-of-function mutations of ATP2A2.
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.|Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
Takumi
T
Nakamura
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
An-A
AA
Kazuno
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
Kazuo
K
Nakajima
Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Ichiro
I
Kusumi
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
Takashi
T
Tsuboi
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
Tadafumi
T
Kato
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D007644:Darier Disease / Q000235:genetics*; D005260:Female; D058685:Genetic Pleiotropy; D006801:Humans; D009154:Mutation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human
ATP2A2; Darier's disease; bipolar disorder; endoplasmic reticulum calcium pump; schizophrenia