1 JAMA Psychiatry 2013 Jun 70: 582-90
PMID 23553203
Title Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families.
Abstract schizophreniais 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 ofschizophreniawill 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 toschizophreniain families with multiple affected individuals withschizophrenia.
We performed genome-wide array comparative genomic hybridization, linkage analysis, and exome sequencing in multiplex families withschizophrenia.
Probands and their family members were recruited from academic medical centers.
We intended to identify rare disease-causing mutations in 5 large families whereschizophreniatransmission 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 inPPEF2, 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 toschizophrenia.
Exome sequencing of multiplex pedigrees uncovers new genes associated with risk for developingschizophreniaand suggests potential novel therapeutic targets.
SCZ Keywords schizophrenia
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