AluY insertion (IVS4-52ins316alu) in the glycerol kinase gene from an individual with benign glycerol kinase deficiency

Zhang, Y.-H.; Dipple, Katrina M.; Vilain, Éric; Huang, Bing; Finlayson, G.; Therrell, Bradford L.; Worley, Kim C.; Deininger, Prescott L.; McCabe, Edward R.B.

doi:10.1002/(sici)1098-1004(200004)15:4<316::aid-humu3>3.0.co;2-9

Cited by 37 publications

(11 citation statements)

References 29 publications

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“…This resulted in deletion of exon 10 (43 bp) and a frameshift predicting a premature stop codon after 307 aa. The fourth patient was previously described (8). He had asymptomatic GKD and an AuY insertion in intron 4 (IVS4-52ins316Alu).…”

Section: Resultsmentioning

confidence: 99%

“…Individual 120104-1 presented at 70 y of age with pseudo-hypertriglyceridemia and asymptomatic GKD. The final individual, 080112-1, with GKD had an Alu Y insertion (IVS4-52ins 316Alu) and has been previously described (8). He had pseudohypertriglyceridemia.…”

Section: Methodsmentioning

confidence: 89%

“…Patients with GKD were referred by outside physicians and informed consent using forms approved by the Institutional Review Boards of UCLA and Baylor College of Medicine was obtained. For each patient, blood samples were collected, a lymphoblastoid cell line (LBL) was established and maintained, and the GK Xp21 sequence including the 21 exons and intron-exon boundaries determined as previously described (8).…”

Section: Methodsmentioning

confidence: 99%

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Asymptomatic Isolated Human Glycerol Kinase Deficiency Associated with Splice-Site Mutations and Nonsense-Mediated Decay of Mutant RNA

et al. 2006

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Isolated glycerol kinase deficiency (GKD) is an Xlinked inborn error of metabolism that is either symptomatic or asymptomatic. GKD is due to deletions of, or mutations within, the GK gene, and there is no genotype-phenotype correlation. We identified three patients with asymptomatic GKD, determined that they had GK splice-site mutations, and studied the stability of their GK mRNA to understand the molecular mechanism of the GKD. All three patient mutations caused a frameshift and introduction of a premature stop codon. A fourth patient had an Alu insertion in intron 4 that led to alternative splicing. To study the effect of splice-site mutations on RNA species, we performed reverse transcriptase PCR and found only normal-sized products for all patients. Incubation with anisomycin to block nonsense-mediated decay (NMD), revealed two RNA species for each individual. Sequence analysis revealed that the larger bands represented the wild-type GK RNA and smaller bands represented mutant misspliced RNA, suggesting that the abnormal RNA species were targeted by NMD. Normal RNA species observed in each patient are likely responsible for their mild phenotypes. We speculate that influences on RNA processing and protein stability represent modifiers of the GKD phenotype. (Pediatr Res 59: 590-592, 2006) I solated GKD is an X-linked inborn error of metabolism (1). We have previously shown that GKD is due to deletions of, or mutations within, the glycerol kinase gene (GK) located on Xp21 that encodes a 524 aa protein (1). Isolated GKD is either asymptomatic or symptomatic with episodes of vomiting, acidosis (metabolic crises), and lethargy that can progress to coma or CNS crises. GKD is caused by large deletions, insertions, missense mutations, nonsense mutations, and splice-site mutations (1-3). Our previous work has shown that there is no genotype-phenotype correlation in GKD (2). We hypothesize that this lack of genotype-phenotype correlation in patients with GKD is due to the role of modifier genes in the GK phenotype (2,4).NMD is a quality-control mechanism naturally occurring in cells to maintain homeostasis and destroy mRNA that contain premature stop codons (5,6). This process is evolutionarily conserved and is found in species from yeast (Saccharomyces cerevisiae) to worms (Caenorhabditis elegans) to humans (5). NMD occurs in the nucleus and cytoplasm (5,6), and evidence suggests that NMD and alternative splicing are coupled (7). Better understanding of this natural process to minimize the effect of DNA mutations in the genome will be important in understanding human disease.The purpose of this investigation was to identify patients with GKD due to splice-site mutations and to determine the effect of the splice-site mutation on the GK mRNA stability. Our results indicate that GKD is one of the many disorders with splice-site mutations and that the aberrant transcripts are targeted for NMD. METHODSIndividuals with isolated GKD. Patient 020518-1 presented with pseudohypertriglyceridemia and asymptomatic GKD. H...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

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Asymptomatic Isolated Human Glycerol Kinase Deficiency Associated with Splice-Site Mutations and Nonsense-Mediated Decay of Mutant RNA

et al. 2006

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“…Very few of these events have been reported. A deletion of 1 base pair in DMD causes Duchenne Muscular Dystrophy (Narita et al, 1993), and a 6-bp deletion in FCMD causes Fukuyama-type congeni- (Meischl et al, 2000) RP2 Xp L1 X-linked retinitis pigmentosa (Schwahn et al, 1998;Ostertag and Kazazian, 2001a) (Miki et al, 1996) FGFR2 10q Alu Apert syndrome (Oldridge et al, 1999) GK Xp Alu Glycerol kinase defiency (Zhang et al, 2000) OPA1 3q Alu Autosomal dominant optic atrophy (Gallus et al, 2010) α-galactosidase A Xq Alu Fabry disease (Kornreich et al, 1990) HEXB 5q Alu Sandhoff disease (Neote et al, 1990) tal muscular dystrophy (Kondo-Iida et al, 1999). Further deletion of PDHX located on chromosome 11 results in pyruvate dehydrogenase-complex deficiency (Miné et al, 2007).…”

Section: Human Diseases and Retroelementsmentioning

confidence: 99%

Retroelements: molecular features and implications for disease

et al. 2013

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Eukaryotic genomes comprise numerous retroelements that have a major impact on the structure and regulation of gene function. Retroelements are regulated by epigenetic controls, and they generate multiple miRNAs that are involved in the induction and progression of genomic instability. Elucidation of the biological roles of retroelements deserves continuous investigation to better understand their evolutionary features and implications for disease.

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“…[40][41][42] Alu insertion/deletion polymorphism has been reported to be in total linkage disequilibrium with CTG repeats in myotonic dystrophy. 43 Several reports [44][45][46][47][48][49] indicate that de novo Alu insertions into intronic sequences in close proximity to the affected exon cause the downstream exon to shift from constitutive splicing to full exon skipping or alternative splicing (Table 2). In our study, this event occurred in a tissue-specific manner, suggesting rather a disruption of pre-existing intronic splicing regulatory elements.…”

Section: Intronic Alterations Affect Splicing Of Capn3 Genementioning

confidence: 99%

CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements

et al. 2011

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Recessive mutations of CAPN3 gene are reported to be responsible for limb girdle muscular dystrophy type 2A (LGMD2A). In all, 15-25% of intronic nucleotide changes identified in this gene were investigated by in silico analysis, but occasionally supported by experimental data or reported in some cases as a polymorphism. We report here genetic and transcriptional analyses in three Tunisian patients belonging to the same consanguineous family sharing the same mutation c.1194-9 A4G and Alu repeats insertion in intron 7 of CAPN3 gene. Reverse transcriptase-PCR experiments performed on total RNA from the patient's muscle biopsy showed retention of the eight last nucleotides of intron 9 in the CAPN3 transcript lacking the first seven exons. Our results provide evidence regarding the potential involvement of Alu elements in aberrant processing of pre-mRNA owing to the disruption of pre-existing intronic splicing regulatory elements. We also demonstrated variable mRNA alternative splicing among tissues and between LGMD2A patients. A deep intronic variation and rearrangement have been reported in the literature as causing genetic diseases in humans. However, this is the first report on a potential pathogenic CAPN3 gene mutation resulting from an Alu insertion.

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AluY insertion (IVS4-52ins316alu) in the glycerol kinase gene from an individual with benign glycerol kinase deficiency

Cited by 37 publications

References 29 publications

Asymptomatic Isolated Human Glycerol Kinase Deficiency Associated with Splice-Site Mutations and Nonsense-Mediated Decay of Mutant RNA

Asymptomatic Isolated Human Glycerol Kinase Deficiency Associated with Splice-Site Mutations and Nonsense-Mediated Decay of Mutant RNA

Retroelements: molecular features and implications for disease

CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements

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