Department of Pathology, University of Washington School of Medicine, Seattle, USA.
JAMA Psychiatry. 2013 Jun;70(6):582-90. doi: 10.1001/jamapsychiatry.2013.1195.
Schizophrenia is a complex genetic disorder demonstrating considerable heritability. Genetic studies have implicated many different genes and pathways, but much of the genetic liability remains unaccounted for. Investigation of genetic forms of schizophrenia will lead to a better understanding of the underlying molecular pathways, which will then enable targeted approaches for disease prevention and treatment.
To identify new genetic factors strongly predisposing to schizophrenia in families with multiple affected individuals with schizophrenia.
We performed genome-wide array comparative genomic hybridization, linkage analysis, and exome sequencing in multiplex families with schizophrenia.
Probands and their family members were recruited from academic medical centers.
We intended to identify rare disease-causing mutations in 5 large families where schizophrenia transmission appears consistent with single-gene inheritance.
Array comparative genomic hybridization was used to identify copy number variants, while exome sequencing was used to identify variants shared in all affected individuals and linkage analysis was used to further filter shared variants of interest. Analysis of select variants was performed in cultured cells to assess their functional consequences.
Rare inherited disease-related genetic mutations.
No segregating rare copy number variants were detected by array comparative genomic hybridization. However, in all 5 families, exome sequencing detected rare protein-altering variants in 1 of 3 genes associated with the N -methyl-D-aspartate (NMDA) receptor. One pedigree shared a missense and frameshift substitution of GRM5, encoding the metabotropic glutamate receptor subtype 5 (mGluR5), which is coupled to the NMDA receptor and potentiates its signaling; the frameshift disrupts binding to the scaffolding protein tamalin and increases mGluR5 internalization. Another pedigree transmitted a missense substitution in PPEF2, encoding a calmodulin-binding protein phosphatase, which we show influences mGluR5 levels. Three pedigrees demonstrated different missense substitutions within LRP1B, encoding a low-density lipoprotein receptor-related protein tied to both the NMDA receptor and located in a chromosome 2q22 region previously strongly linked to schizophrenia.
Exome sequencing of multiplex pedigrees uncovers new genes associated with risk for developing schizophrenia and suggests potential novel therapeutic targets.
精神分裂症是一种复杂的遗传疾病，具有相当大的遗传性。遗传研究已经涉及到许多不同的基因和途径，但大部分遗传易感性仍然无法解释。对精神分裂症的遗传形式的研究将导致对潜在分子途径的更好理解，这将使我们能够针对疾病预防和治疗采取有针对性的方法。
在有多个精神分裂症患者的家系中，确定新的遗传因素，这些遗传因素强烈导致精神分裂症。
我们在家系中进行了全基因组芯片比较基因组杂交、连锁分析和外显子测序。
从学术医疗中心招募先证者及其家庭成员。
我们打算在 5 个大型家系中识别罕见的致病突变，这些家系的精神分裂症遗传模式符合单基因遗传。
使用芯片比较基因组杂交来识别拷贝数变异，同时使用外显子测序来识别所有受影响个体共有的变异，使用连锁分析进一步筛选感兴趣的共有的变异。对选定变异的分析是在培养细胞中进行的，以评估其功能后果。
罕见的遗传性疾病相关基因突变。
通过芯片比较基因组杂交没有检测到分离的罕见拷贝数变异。然而，在所有 5 个家系中，外显子测序在 3 个与 N -甲基-D-天冬氨酸（NMDA）受体相关的基因之一中检测到罕见的蛋白改变变异。一个家系共享一个错义突变和移码突变GRM5，编码代谢型谷氨酸受体亚型 5（mGluR5），与 NMDA 受体偶联并增强其信号；移码突变破坏了与支架蛋白 tamalin 的结合，并增加了 mGluR5 的内化。另一个家系传递了一个错义突变PPEF2，编码一种钙调蛋白结合蛋白磷酸酶，我们证明它影响 mGluR5 水平。三个家系表现出 LRP1B 内不同的错义突变，LRP1B 编码一种低密度脂蛋白受体相关蛋白，与 NMDA 受体相关，位于染色体 2q22 区域，该区域以前与精神分裂症强烈相关。
对多系家系的外显子组测序揭示了与精神分裂症发病风险相关的新基因，并提出了潜在的新治疗靶点。
