Dataset Information

De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant.

ABSTRACT: Aim: We previously performed the first trio-based exome study for bipolar disorder and identified 71 de novo mutations. Among these mutations, the only mutation located at the splice donor site was in UNC13B. We focused on and analyzed the functions of the mutation.

Methods: In order to analyze the functional alterations, due to the mutation, we performed a minigene splicing assay.

Key results: We found that the mutation caused the loss of a wild-type splicing variant, which was consistent with the computational splice prediction, and that an exon-skipping variant increased significantly. The exon-skipping variant also existed in the wild-type minigene, although it was rare. Hence, we validated the expression of the exon-skipping variant using total RNAs derived from the human cerebral cortex. We showed the possibility that the exon-skipping variant was rare, but expressed even in those that do not carry the mutation.

Conclusions: Based on our results, we suggest that an abnormal splicing pattern of UNC13B occurred in the patient, which could be related to the pathophysiology of bipolar disorder.

SUBMITTER: Nakamura T

PROVIDER: S-EPMC7292303 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant.

Nakamura Takumi T Jimbo Kotori K Nakajima Kazuo K Tsuboi Takashi T Kato Tadafumi T

Neuropsychopharmacology reports 20180817 4

<h4>Aim</h4>We previously performed the first trio-based exome study for bipolar disorder and identified 71 de novo mutations. Among these mutations, the only mutation located at the splice donor site was in UNC13B. We focused on and analyzed the functions of the mutation.<h4>Methods</h4>In order to analyze the functional alterations, due to the mutation, we performed a minigene splicing assay.<h4>Key results</h4>We found that the mutation caused the loss of a wild-type splicing variant, which w ...[more]

PMID: 30117296

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Project description:BackgroundPulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined.MethodsTo identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource - Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD.ResultsSeven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e-5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development.ConclusionsRare variant analysis of a large international consortium identified two new candidate genes-FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

Dataset Information

De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant.

Publications

De novo UNC13B mutation identified in a bipolar disorder patient increases a rare exon-skipping variant.

Similar Datasets

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