Characterization of the Effects of Mutations in the Putative Branchpoint Sequence of Intron 4 on the Splicing within the Human Lecithin:cholesterol Acyltransferase Gene

Li, Min; Pritchard, P H

doi:10.1074/jbc.m910197199

Cited by 30 publications

(21 citation statements)

References 32 publications

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“…The branchpoint consensus (YNYYRAY, where Y = pyrimidine, R = purine, N = any nucleotide, A = adenine) is important in intron excision at the 3Ј splice acceptor site. 44 The putative natural branchpoint site is also a 6/7 match to the consensus. Whether the −49 mutation results in the creation of a 'cryptic' branchpoint site and influences splicing remains to be determined.…”

Section: Resultsmentioning

confidence: 99%

Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder

et al. 2001

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Genes involved in the regulation of synaptic vesicle function are potential candidates for the development of psychiatric disorders. In addition to experimental and theoretical considerations, a number of genes involved in synaptic vesicle function map to regions of the genome that have been linked to bipolar disorder (BPD) and schizophrenia (SZ). One is synaptojanin 1 (SYNJ1) which maps to 21q22.2, a chromosomal region that has been linked to BPD in a subset of families in several studies. Synaptojanin 1 is an inositol 5-phosphatase that has an important role in synaptic vesicle endocytosis. Mutation screening of 32 exons, intron-exon junctions, and 839 bases of 5Ј-flanking DNA resulted in the identification of 11 mutations of which four were very common and seven were very rare. Of the 11 mutations identified, several may have functional significance including two coding variants, two that may affect the binding of a transcription factor, and two that involve known splicing regulatory domains. Five bipolar patients out of 149 analyzed were found who have one of the four rare variants that were most likely to have functional significance compared with 0/148 controls. The allele frequencies for three of the four common variants were very similar in bipolar patients and controls. A slight difference in allele frequency was found for an interesting mutation we detected in intron 12 in which two non-adjacent thymidine residues are deleted in a poly-AT tract located near the exon 12 splice donor site ( 2 = 2.45, P = 0.12, 2-tailed). Although we failed to unequivocally identify a specific SYNJ1 allele that could be responsible for putative chromosome 21q22-linked BPD, several interesting variants were found to be increased in bipolar subjects and should be further investigated. Molecular Psychiatry (2001) 6, 387-395.

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Section: Resultsmentioning

confidence: 99%

Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder

et al. 2001

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“…26,27 Markedly reduced levels of mutant transcript may occur despite the absence of a premature termination codon that would stimulate nonsensemediated RNA decay through reduced splicing efficiency. 28 This child developed signs of HHT at 8 years of age but had initially presented with typical features of PAH, including a high pulmonary vascular resistance, at 3 months of age. HHT-related PAH has previously been reported, albeit predominantly in association with mutations in ALK-1.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Receptor Mutations and Pulmonary Arterial Hypertension in Childhood

Berger²,

et al. 2005

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Background-Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age.Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. Methods and Results-We performed mutation analysis in genes encoding receptor members of the transforming growth factor-␤ cell-signaling pathway in 18 children (age at presentation Ͻ6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) (age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (nϭ2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. Conclusions-The

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“…This variant is a cytosine insertion that maps to a putative branch point site [40] and results in an increase in the distance between this site and the 3 splice site. Studies have pointed to the importance of the conserved intronic branch point sequence and the distance between the branch point and the splice sites in gene splicing [39,40,[63][64][65][66] . Exon 9 skipping of the cystic fi brosis transmembrane conductance regulator gene is a well-characterized example, whereby the length of a polypyrimidine tract between the branch point adenine and the 3 splice acceptor can be correlated with the frequency of exon skipping and disease phenotype [67] .…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia

et al. 2005

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Tetrahydrobiopterin (BH₄) is a vital cofactor maintaining availability of the amine neurotransmitters [dopamine (DA), noradrenaline (NA), and serotonin (5-HT)], regulating the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS), and stimulating and modulating the glutamatergic system (directly and indirectly). These BH₄ properties and their potential relevance to schizophrenia led us to investigate the hypothesis of a study group (healthy controls, n = 37; schizophrenics, n = 154) effect on fasting plasma total biopterin levels (a measure of BH₄). Study analysis showed a highly significant deficit of total biopterins for the schizophrenic sample after partialling out the effects of potential confounds of gender, age, ethnicity, neuroleptic use history and dose of current use, 24-hour dietary phenylalanine/protein ratio (a dietary variable relevant to BH₄ synthesis), and plasma phenylalanine (which stimulates BH₄ synthesis). A mean decrement of 34% in plasma total biopterins for schizophrenics from control values supports clinical relevance for the finding. In a subsample (21 controls and 23 schizophrenics), sequence analysis was done of the GTP cyclohydrolase I feedback regulatory gene and no mutations were found in the coding region of the gene. A deficiency of BH₄ could lead to hypofunction of the systems of DA, NA, 5-HT, NOS/NO, and glutamate, all of which have been independently implicated in schizophrenia psychopathology. Further, evidence has been accumulating which implicates the critical interdependence of these neurotransmitter systems in schizophrenia; this concept, along with the present study finding of a biopterin deficit, suggests that further study of the BH₄ system in schizophrenia is warranted and desirable.

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Characterization of the Effects of Mutations in the Putative Branchpoint Sequence of Intron 4 on the Splicing within the Human Lecithin:cholesterol Acyltransferase Gene

Cited by 30 publications

References 32 publications

Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder

Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder

Transforming Growth Factor-β Receptor Mutations and Pulmonary Arterial Hypertension in Childhood

Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia

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