Identification of Alu-mediated, large deletion-spanning exons 2–4 in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency

Zhang, Gaixiu; Fukao, Toshiyuki; Sakurai, Satomi; Yamada, Keitaro; Gibson, K. Michael; Kondo, Naomi

doi:10.1016/j.ymgme.2006.06.010

Cited by 28 publications

(23 citation statements)

References 20 publications

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“…The following mechanisms regarding Alu-mediated genetic disorders have been demonstrated: (i) deleted and duplicated allele is induced by homologous recombination between different Alu sequences mainly in introns; 15,16 (ii) inactivation of genes is induced by insertion of Alu sequences into genes, in particular, into exons; 17 and (iii) variant Alu sequences in introns induce exonization. 18 In particular, because Alu sequences share high homology with each other and their length is ~300 bases although they have grown in diversity along the course of evolution, the different Alu sequences are subject to homologous recombination.…”

Section: Original Research Articlementioning

confidence: 99%

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Kataoka

Aimi

Yanagisawa

et al. 2013

Genetics in Medicine

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Original research articlePulmonary arterial hypertension (PAH) is a serious disease with a poor prognosis. Possible etiological factors for PAH development include vasospasm, endothelin overactivity, intimal hyperplasia due to increased growth factor secretion, and thrombus formation in small pulmonary arteries.1 The presence of familial disease in ~6% of PAH patients with no obvious secondary causes of PAH suggested that genetic factors play an important role in a substantial proportion of patients with PAH. Linkage analysis and positional cloning have identified mutations in the bone morphogenetic protein type 2 receptor (BMPR2) gene in ~60% of familial PAH (FPAH) cases and 10-40% of patients with idiopathic PAH (IPAH).2-4 BMPR2 mutations were also reported in FPAH patients and in 40% of the IPAH cases in a Japanese population, 5 corresponding to the clinical observation that PAH prevalence does not vary among different races. 6 Recent studies have clarified the presence of genome-wide copy-number variations caused by genomic rearrangement such as deletion, duplication, inversion, and translocation of genetic codes spanning more than 1,000 base pairs, with genetic rearrangements of BMPR2 in patients with FPAH resulting in deletion or duplication of one or more exons of the gene. 7,8 Another study identified exonic deletion or duplication in BMPR2 in both FPAH and IPAH cases.9 These findings have demonstrated that BMPR2 mutations may account for a higher proportion of PAH patients than previously expected.Genome-wide analysis of copy-number variations has indicated significant variation in distribution and frequency among populations with different ethnic backgrounds, although such information about the genetic rearrangements of BMPR2 has been limited to the data obtained. Furthermore, deletion break points in exonic deletions of BMPR2 have not been reported. We therefore undertook a thorough genetic analysis of BMPR2 in Japanese patients with PAH and investigated the deletion break points in exonic deletions of BMPR2. MATERIALS AND METHODS Study populationThe study included PAH patients and their family members in Kyorin University Hospital, Tokyo, Japan, who were enrolled Purpose: The purpose of this study was to undertake thorough genetic analysis of the bone morphogenetic protein type 2 receptor (BMPR2) gene in patients with pulmonary arterial hypertension. Methods:We conducted a systematic analysis for larger gene rearrangements together with conventional mutation analysis in 152 pulmonary arterial hypertension patients including 43 patients diagnosed as having idiopathic pulmonary arterial hypertension and 10 diagnosed as having familial pulmonary arterial hypertension.Results: Analysis of the BMPR2 gene revealed each of the four kinds of nonsense and frameshift mutations, one missense mutation, one splice-site mutation, and two types of exonic deletion. For cases in which exons 1-3 were deleted, the 5′ and 3′ break points were located in the AluY repeat sequences in the 5′ side of the adjacent NOP58 gene...

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Section: Original Research Articlementioning

confidence: 99%

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Kataoka

Aimi

Yanagisawa

et al. 2013

Genetics in Medicine

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“…c.731–46_752del (a 68‐bp deletion) involves the splice acceptor site of intron 7, causing exon 8 skipping (Fukao, Song, et al, ). The other three variants could be attributed to Alu elements‐mediated unequal homologous recombination (Fukao et al, , ; Zhang et al, ). We established multiplex ligation‐dependent probe amplification (MLPA) analysis for ACAT1 , which is useful to identify these large gene rearrangements (Fukao et al, ).…”

Section: Disease‐associated Acat1 Variantsmentioning

confidence: 99%

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

et al. 2019

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Mitochondrial acetoacetyl‐CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. It typically manifests with episodic ketoacidosis. The presence of isoleucine‐derived metabolites is the key marker for biochemical diagnosis. To date, 105 ACAT1 variants have been reported in 149 T2‐deficient patients. The 56 disease‐associated missense ACAT1 variants have been mapped onto the crystal structure of T2. Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability. Expression and activity data of 30 disease‐associated missense ACAT1 variants have been measured by expressing them in human SV40‐transformed fibroblasts. Only two variants (p.Cys126Ser and p.Tyr219His) appear to have equal stability as wild‐type. For these variants, which are inactive, the side chains point into the active site. In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening.

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“…T2 deficiency is caused by mutations in the ACAT1 (T2) gene located on chromosome 11q22.3-q23.1 (Fukao et al 1990; Kano et al 1991). T2 deficiency is very heterogeneous at the genotype level, with at least 50 different mutations described (Fukao et al , 1997(Fukao et al , 1998(Fukao et al , 2002(Fukao et al , 2003(Fukao et al , 2008(Fukao et al , 2010aWakazono et al 1995;Nakamura et al 2001;Zhang et al 2004Zhang et al , 2006Sakurai et al 2007). …”

Section: Introductionmentioning

confidence: 99%

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1

et al. 2011

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Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects both isoleucine catabolism and ketone body metabolism. The disorder is characterized by intermittent ketoacidotic episodes. We report three Japanese patients. One patient (GK69) experienced two ketoacidotic episodes at the age of 9 months and 3 years, and no further episodes until the age of 25 years. She had two uncomplicated pregnancies. GK69 was a compound heterozygote of the c.431A>C (H144P) and c.1168T>C (S390P) mutations in T2 (ACAT1) gene. She was not suspected of having T2 deficiency during her childhood, but she was diagnosed as T2 deficient at the age of 25 years by enzyme assay using fibroblasts. The other two patients were identical twin siblings who presented their first ketoacidotic crisis simultaneously at the age of 3 years 4 months. One of them (GK77b) died during the first crisis and the other (GK77) survived. Even during severe crises, C5-OH and C5:1 were within normal ranges in their blood acylcarnitine profiles and trace amounts of tiglylglycine and small amounts of 2-methyl-3-hydroxybutyrate were detected in their urinary organic acid profiles. They were H144P homozygotes. This H144P mutation has retained the highest residual T2 activity in the transient expression analysis of mutant cDNA thus far, while the S390P mutation did not retain any residual T2 activity. The "mild" H144P mutation may result in subtle profiles in blood acylcarnitine and urinary organic acid analyses. T2-deficient patients with "mild" mutations have severe ketoacidotic crises but their chemical phenotypes may be subtle even during acute crises.JIMD Reports

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Identification of Alu-mediated, large deletion-spanning exons 2–4 in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency

Cited by 28 publications

References 20 publications

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Alu-mediated nonallelic homologous and nonhomologous recombination in the BMPR2 gene in heritable pulmonary arterial hypertension

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1

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