Exon 10 skipping caused by intron 10 splice donor site mutation in cholesteryl ester transfer protein gene results in abnormal downstream splice site selection

Sakai, Naohiko; Santamarina-Fojo, Silvia; Yamashita, Shizuya; Matsuzawa, Yūji; Brewer, H. Bryan

doi:10.1016/s0022-2275(20)37289-8

Cited by 42 publications

(8 citation statements)

References 45 publications

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“…In fact, a very similar mutation was recently reported in the cholesteryl ester transfer protein (CETP) gene which leads to a deficiency of the CETP (20). The mutation in the CETP gene in the 5Ј splice junction resulted in exon 10 skipping (20). We also identified a second mutation at the ϩ5 position of the 5Ј splice site in the intron spanning exon 13 and exon 14.…”

Section: Discussionsupporting

confidence: 72%

“…There are many documented cases in which a mutation at this position causes aberrant splicing that results in skipping of upstream exons (19). In fact, a very similar mutation was recently reported in the cholesteryl ester transfer protein (CETP) gene which leads to a deficiency of the CETP (20). The mutation in the CETP gene in the 5Ј splice junction resulted in exon 10 skipping (20).…”

Section: Discussionmentioning

confidence: 87%

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Splice donor site mutations in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene cause a deficiency of the endoplasmic reticulum 3-hydroxy-3-methylglutaryl coenzyme A reductase protein in UT2 cells

Engfelt

Masuda

Paton

et al. 1998

Journal of Lipid Research

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UT2 cells are a mutant clone of Chinese hamster ovary (CHO) cells that are deficient in the 97 kDa endoplasmic reticulum (ER) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase protein. The analysis of UT2 cell cDNA and genomic DNA has led to the identification of two novel point mutations in intronic sequences of the ER HMG-CoA reductase gene. One mutation identified at the ؉ 1 position (G → A) of the 5 splice site of exon 11-12 junction was shown to cause exon 11 skipping which resulted in the insertion of premature stop codons. We also identified a second mutation at the ؉ 5 position (G → A) of the 5 splice site in the intron spanning exons 13 and 14. Furthermore, the data indicate that the two mutations in the reductase gene are present on the same allele. As demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) of UT2 cell mRNA, the mutations produce aberrant spliced messages. If the aberrant messages were translated, truncated proteins of 44 kDa or 66 kDa would be predicted. More importantly, these truncated proteins would be expected not to have catalytic activity. In addition, we have also recently demonstrated that the UT2 cells express a 90 kDa HMG-CoA reductase protein that is localized exclusively in peroxisomes, and is up-regulated when the cells are grown in the absence of added mevalonate. Thus, the mutations identified in the ER reductase gene in UT2 cells indicate that neither a 97 kDa nor a 90 kDa reductase protein can be produced from this gene.-Engfelt, W. H., K. R. Masuda, V. G. Paton, and S. K. Krisans. Splice donor site mutations in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene cause a deficiency of the endoplasmic reticulum 3-hydroxy-3-methylglutaryl coenzyme A reductase protein in UT2 cells.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 87%

Splice donor site mutations in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene cause a deficiency of the endoplasmic reticulum 3-hydroxy-3-methylglutaryl coenzyme A reductase protein in UT2 cells

Engfelt

Masuda

Paton

et al. 1998

Journal of Lipid Research

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“…Single mutations in intronic or exonic DNA motor cortex, with use of hematoxylin and eosin to evaluate motor have been found to result in exon-skipping and intronneuron loss, and with myelin stains (Luxol-fast blue) to establish corticospinal tract degeneration. SOD1 mutation analysis was per-retention (Kuivenhoven et al, 1996;Sakai et al, 1996; formed by R. H. Brown, Harvard University. Pathologically confirmed Wang et al, 1996).…”

Section: Eaat2 Transcripts?mentioning

confidence: 99%

Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis

Lin

Bristol

Jin

et al. 1998

Neuron

631

352

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by selective upper and lower motor neuron degeneration, the pathogenesis of which is unknown. About 60%-70% of sporadic ALS patients have a 30%-95% loss of the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2) protein in motor cortex and spinal cord. Loss of EAAT2 leads to increased extracellular glutamate and excitotoxic neuronal degeneration. Multiple abnormal EAAT2 mRNAs, including intron-retention and exon-skipping, have now been identified from the affected areas of ALS patients. The aberrant mRNAs were highly abundant and were found only in neuropathologically affected areas of ALS patients but not in other brain regions. They were found in 65% of sporadic ALS patients but were not found in nonneurologic disease or other disease controls. They were also detectable in the cerebrospinal fluid (CSF) of living ALS patients, early in the disease. In vitro expression studies suggest that proteins translated from these aberrant mRNAs may undergo rapid degradation and/ or produce a dominant negative effect on normal EAAT2 resulting in loss of protein and activity. These findings suggest that the loss of EAAT2 in ALS is due to aberrant mRNA and that these aberrant mRNAs could result from RNA processing errors. Aberrant RNA processing could be important in the pathophysiology of neurodegenerative disease and in excitotoxicity. The presence of these mRNA species in ALS CSF may have diagnostic utility.

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“…The two most common CETP mutations known to date, the D442G (8) and the intron 14 splicing (9) mutations affect about 7 and 2% of the general Japanese population, respectively (10). Recently, other less common mutations have also been described (11)(12)(13). No common CETP gene mutations have been described in European populations.…”

mentioning

confidence: 99%

Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia

Bruce

Sharp

Tall

1998

Journal of Lipid Research

135

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Plasma triglyceride (TG) levels are inversely related to HDL-cholesterol levels and subjects with high TG and low HDL cholesterol have increased coronary heart disease (CHD) risk. Plasma cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to TG-rich lipoproteins. In this study we determined the relationship between a common CETP amino acid polymorphism (I405V) and CETP and HDL levels and CHD prevalence in 576 men of Japanese ancestry in the Honolulu Heart Program cohort. This conservative substitution was associated with altered plasma CETP concentration (1.95 ؎ 0.54, 1.91 ؎ 0.57, and 1.77 ؎ 0.57 g/ml for the II , IV and VV genotypes, respectively). The distribution of plasma CETP concentrations among the VV , but not II , men appeared bimodal ( P Ͻ 0.01), suggesting the presence of a functionally significant CETP gene mutation(s) in a subset of V alleles. HDL-C levels were higher in VV than IV for II men (55.4 ؎ 17.4, 51.3 ؎ 16.6, 51.1 ؎ 17.0 mg/dl, P Ͻ 0.04). However, the increase in HDL was only significant in VV men with plasma TG Ͼ 165 mg/dl. Although CHD prevalence was not significantly different among the three genotypes in this population, in the subpopulation with high plasma TG, CHD prevalence appeared higher among VV than IV or II subjects (38% vs. 27% vs. 18%, P Ͻ 0.05 for an interaction of genotype and plasma TG levels). In fresh plasma from a separate group of normolipidemic subjects, the V/I polymorphism was not associated with any change in plasma CETP specific activity.The data suggest that a widespread and common CETP gene mutation(s) in linkage disequilibrium with 405V causes low CETP. Among hypertriglyceridemic men this is associated with higher HDL and possibly with increased CHD.-Bruce, C., D. S. Sharp, and A. R. Tall. Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia.

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Exon 10 skipping caused by intron 10 splice donor site mutation in cholesteryl ester transfer protein gene results in abnormal downstream splice site selection

Cited by 42 publications

References 45 publications

Splice donor site mutations in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene cause a deficiency of the endoplasmic reticulum 3-hydroxy-3-methylglutaryl coenzyme A reductase protein in UT2 cells

Splice donor site mutations in the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene cause a deficiency of the endoplasmic reticulum 3-hydroxy-3-methylglutaryl coenzyme A reductase protein in UT2 cells

Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis

Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia

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