Elevated DISC1 transcript levels in PBMCs during acute psychosis in patients with schizophrenia.

BACKGROUND: Severe mental disorders like schizophrenia are a leading cause of disability in people in the prime years of their lives (aged 15 to 44 years). Relapse is a primary contributor to schizophrenia disease burden and is frequently attributed to medication noncompliance and inadequate doses. Currently, a patient's neuroleptic dose is titrated to clinical response within recommended dose ranges. Use of unbiased biomarkers of effective neuroleptic treatment-response would greatly facilitate the identification of a person's lowest effective dose to minimize unsafe side effects and improve compliance. Biomarkers may allow precisely tailored adjustments of neuroleptic dose to reduce relapse due to variable disease course. METHODS AND FINDINGS: Biomarkers of active psychosis were sought among persons with schizophrenia hospitalized with acute psychosis. The transcriptional response of peripheral blood mononuclear cells (PBMCs) to treatment of psychosis was measured using RNA expression profiling in 12-paired samples from patients with schizophrenia. The paired samples were collected early after treatment initiation and again just before patients were released from the hospital. Patients showed significant improvement in positive symptoms of psychosis assessed at each sample collection using a brief psychiatric rating scale (BPRS) (P<0.05). Preliminary evidence is presented indicating that decreased transcript levels of isoforms of disrupted in schizophrenia 1 (DISC1) measured in PBMCs were associated with treatment in 91% of samples (P=0.037). CONCLUSION: Further studies are warranted to identify neuroleptic-response biomarkers and to replicate this initial finding of association of DISC1 transcript levels with treatment of psychosis.

Cerebral cavernous malformations: somatic mutations in vascular endothelial cells.

OBJECTIVE: Germline mutations in 3 genes have been found in familial cases of cerebral cavernous malformations (CCMs). We previously discovered somatic and germline truncating mutations in the KRIT1 gene, supporting the "2-hit" mechanism of CCM lesion formation in a single lesion. The purpose of this study was to screen for somatic, nonheritable mutations in 3 more lesions from different patients and identify the cell type(s) in which somatic mutations occur. METHODS: Somatic mutations were sought in DNA from 3 surgically excised, fresh-frozen CCM lesions by cloning and screening polymerase chain reaction products generated from KRIT1 or PDCD10 coding regions. Laser capture microdissection was used on isolated endothelial and nonendothelial cells to determine whether somatic mutations were found in endothelial cells. RESULTS: CCM lesions harbor somatic and germline KRIT1 mutations on different chromosomes and are therefore biallelic. Both mutations are predicted to truncate the protein. The KRIT1 somatic mutations (novel c.1800delG mutation and previously identified 34 nucleotide deletion) in CCMs from 2 different patients were found only in the vascular endothelial cells lining caverns. No obvious somatic mutations were identified in the 2 other lesions; however, the results were inconclusive, possibly owing to the technical limitations or the fact that these specimens had a small proportion of vascular endothelial cells lining pristine caverns. CONCLUSION: The "2-hit" mechanism occurs in vascular endothelial cells lining CCM caverns from 2 patients with somatic and Hispanic-American KRIT1 germline mutations. Methods for somatic mutation detection should focus on vascular endothelial cells lining pristine caverns.

Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion.

BACKGROUND AND PURPOSE: Cerebral cavernous malformations (CCMs) are focal dysmorphic blood vessel anomalies that predispose patients to hemorrhagic stroke and epilepsy. CCMs are sporadic or inherited and 3 genes (CCM1, CCM2, and CCM3) have been identified. However, the role of somatic mutation in CCM genesis has been disputed. The hypothesis that somatic mutations contribute to CCM lesion genesis is tested. METHODS: Mutations were identified by analysis of polymerase chain reaction (PCR) products spanning the 16 CCM1 coding exons with denaturing high-pressure liquid chromatography (DHPLC), cloning, and sequencing. Somatic mutation was verified 3 ways in lesion DNA and RNA samples. The somatic and germ line mutations were shown to be biallelic using allele specific reverse-transcribed PCR amplification and sequence analyses. RESULTS: A somatic 34-nucleotide deletion in CCM1 is identified in a CCM lesion along with a germ line CCM1 mutation (Q455X). The somatic mutation is not present in DNA or RNA isolated from the patient's blood. These 2 genetic hits are biallelic. CONCLUSIONS: Identification of biallelic CCM1 somatic and germ line truncating mutations strongly support the "two-hit" mechanism in this CCM lesion.