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.
Psychiatry Clin Neurosci. 2016 Aug;70(8):342-50. doi: 10.1111/pcn.12395. Epub 2016 Jun 3.
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.
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.
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.
These results suggest that psychoses in Darier's disease may be caused by a pleiotropic effect of loss-of-function mutations of ATP2A2.
尽管遗传因素在包括双相情感障碍（BD）和精神分裂症在内的精神疾病的病理生理学中起着重要作用，但缺乏明确的致病基因突变阻碍了它们的神经生物学研究。 Darier 病是一种常染色体显性遗传性皮肤病，由染色体 12q23-24.1 上的 ATP2A2 基因突变引起，该基因编码肌浆/内质网钙转运 ATP 酶 2（SERCA2）。据报道，Darier 病与 BD 共分离。最近的全基因组关联研究表明精神分裂症与 ATP2A2 相关。
我们对一名新诊断为 Darier 病和 BD 的患者的 ATP2A2 所有编码区进行了测序。此外，我们进行了文献综述，以检查是否存在可能导致基因失活（LGD）的突变与精神疾病有关。
我们在该患者的 10 号内含子 3'末端发现了一个罕见的杂合突变 c.1288-6A>G。一个微小基因拼接试验表明，该突变引入了一个新的剪接位点，导致移码和过早的终止密码子。对 Darier 病伴发精神疾病的病例报告文献的综述表明，这些病例中携带的 LGD 突变导致移码、改变剪接、获得终止密码子或丢失起始密码子的比率明显高于未报告精神疾病共病的 ATP2A2 突变（11 例中有 9 例，237 例中有 107 例，P=0.026）。在伴有 Darier 病和 BD 的患者中报道的唯一非 LGD 突变（p.C560R）导致 ATP2A2 蛋白表达减少。
这些结果表明，Darier 病中的精神疾病可能是由 ATP2A2 功能丧失突变的多效性效应引起的。
