A Novel Missense Mutation in the Transmembrane Domain of Neuregulin 1 is Associated with Schizophrenia

Walss‐Bass, Consuelo; Liu, Wei; Lew, Debbie F.; Villegas, Ramón; Montero, Patricia Milanés; Dassori, Albana M; Leach, Robin J.; Almasy, Laura; Escamilla, Michael; Raventós, Henriette

doi:10.1016/j.biopsych.2006.03.017

Cited by 103 publications

(89 citation statements)

References 28 publications

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“…Of note, however, is that the frequency of this allele in our control group is consistent with other published studies examining this polymorphism. 46,47 Also noted in the literature is that this allele is rare, if not totally absent, from some Asian populations, so variations in allele frequency, as we observed here, are not unexpected. Further, given the rareness and difficulty of recruiting COS patients, the observed allele frequency may be a spurious finding reflective of the small sample, which might likely change if we were able to collect larger numbers.…”

Section: Discussionsupporting

confidence: 82%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P = 0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

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Section: Discussionsupporting

confidence: 82%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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“…Neuregulin 1 (NRG1) has been associated with an increased risk to develop schizophrenia ( [27] and [35]; meta-analyses: [23], [26] and [30]). The protein is involved in axon guidance, myelination, and synapse formation.…”

Section: Introductionmentioning

confidence: 99%

“…Alternative promoter usage results in numerous splice variant types and more than 30 isoforms [11] and [21]. The isoform variants most commonly expressed in the brain contain a transmembrane domain [10], [11] and [35].…”

Section: Introductionmentioning

confidence: 99%

The response of neuregulin 1 mutant mice to acute restraint stress

Chesworth

Yulyaningsih

Cappas

et al. 2012

Neuroscience Letters

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Stress plays a role in the development and severity of psychotic symptoms and there may be a genetic component to stress vulnerability in schizophrenia. Using an established mouse model for schizophrenia, we investigated the behavioural and endocrine response of Nrg1 transmembrane domain mutant mice (Nrg1 HET) and wild type-like (WT) littermates to acute restraint stress. Animals were screened at 3-4 months and 6-7 months of age (before and after onset of hyperlocomotion) for open field behaviour and serum corticosterone levels. In younger mice, stress reduced locomotive and explorative measures and increased anxietylike behaviour regardless of genotype. Older Nrg1 mutants were less susceptible to the effects of stress on anxiety-related behaviours. All mice responded to restraint stress with robust increases in serum corticosterone. Importantly, the stress-induced increase in corticosterone was more pronounced in Nrg1 mutant than WT mice at the younger but not the older age. Our results suggest that transmembrane domain Nrg1 has only a moderate effect on the acute stress response of mice. The behavioural differences detected between WT and Nrg1 HET mice at the older age were evident without parallel modifications to the glucocorticoid system.

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“…[41][42][43][44][45][46][47][48][49] This TGF-beta pathway is indirectly linked to activation by proteins encoded by the NRG1 gene, 50 another strong candidate gene for psychotic-related disorders in the CVCR. [50][51][52][53][54][55][56][57] The genes encoding for the effectors of this pathway (SMAD2 and SMAD4) are both in chromosome 18 and SMAD4 is located in a region for which we have also found association to psychosis in the CVCR population. 58 The interplay of a variety of transcription factors like homeoproteins plays an important role in the regulated, tissue-specific and developmental expression of eukaryotic genes.…”

Section: Resultsmentioning

confidence: 66%

“…4 However, the current evidence of overlap of genetic susceptibility for SC and BP has led to the question of whether the understanding of a common pathophysiology of psychotic-related disorders will lead to a change in the way we classify these disorders. [5][6][7] We have previously used psychosis as a phenotype for association studies of different regions of the genome [8][9][10] using subjects from the Central Valley of Costa Rica (CVCR). We have found in this population evidence of association of psychosis with three loci on chromosome 18.…”

Section: Introductionmentioning

confidence: 99%

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p

et al. 2007

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Schizophrenia (SC) and bipolar disorder (BP) share many clinical features, among them psychosis. We previously identified a putative gene locus for psychosis on chromosome 18p in a sample from the Central Valley of Costa Rica (CVCR) population. The present study replicated the association to a specific allele of microsatellite marker D18S63 on 18p11.3, using a newly collected sample from the CVCR. A combined analysis of both samples, plus additional subjects, showed that this specific allele on D18S63, which lies within an intron on the TGFB-induced factor (TGIF ) gene, is strongly associated (P-value = 0.0005) with psychosis. Eleven additional SNP markers, spanning five genes in the region, were analyzed in the combined sample from the CVCR. Only the four SNPs within the TGIF gene were in strong linkage disequilibrium with D18S63 (D 0 = 1.00). A specific haplotype for all five markers within the TGIF gene showed evidence of association (P-value = 0.011) to psychosis. A second, distinct haplotype, containing a newly identified nonsynonymous polymorphism in exon 5 of the TGIF gene, showed a nonsignificant trend towards association to psychosis (P-value = 0.077). TGIF is involved in neurodevelopment, neuron survival and controls the expression of dopamine receptors. Altogether, our results point to the possible involvement of TGIF in the pathophysiology of psychotic disorders in the CVCR population.

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A Novel Missense Mutation in the Transmembrane Domain of Neuregulin 1 is Associated with Schizophrenia

Cited by 103 publications

References 28 publications

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

The response of neuregulin 1 mutant mice to acute restraint stress

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p

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