NA20266
DNA from Fibroblast
Description:
LONG-CHAIN 3-HYDROXYACYL-CoA DEHYDROGENASE DEFICIENCY
HYDROXYACYL-CoA DEHYDROGENASE/3-KETOACYL-CoA THIOLASE/ENOYL-CoA HYDRATASE, ALPHA SUBUNIT; HADHA
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases |
| Class |
Disorders of Lipid Metabolism |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
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Biopsy Source
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Unspecified
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Cell Type
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Fibroblast
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Tissue Type
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Skin
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Transformant
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Untransformed
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Sample Source
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DNA from Fibroblast
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Race
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White
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Relation to Proband
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proband
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Confirmation
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Molecular characterization before cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin confirmed by LINE assay |
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| long-chain-3-hydroxyacyl-CoA dehydrogenase |
According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 1.1.1.211; 15% activity. |
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| Gene |
HADHA |
| Chromosomal Location |
2p23 |
| Allelic Variant 1 |
600890.0001; LCHAD DEFICIENCY |
| Identified Mutation |
GLU510GLN; LCHAD DEFICIENCY WITH MATERNAL ACUTE FATTY LIVER OF PREGNANCY, INCLUDED
HADHA, GLU510GLN [dbSNP:rs137852769] [ClinVar]
Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) had designated the mutation GLU474GLN (E474Q) based on numbering of the mature protein.
IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution, in approximately 87% of the chromosomes in patients with LCHAD deficiency (609016).
Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase to determine the molecular basis of LCHAD deficiency in 3 families in which children presented with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mother had acute fatty liver and associated severe complications during pregnancy. The analysis in 2 affected children demonstrated homozygosity for the E474Q mutation. The third child was compound heterozygous for E474Q and Q342X (600890.0002).
IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q mutation in genomic DNA. Functional expression studies in S. cerevisiae showed that the mutation is directly responsible for the loss of LCHAD activity.
Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency due to a homozygous E474Q mutation. The patients had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Recurrent metabolic crises had occurred in 7 patients; the other 6 had a steadily progressive course. Cholestatic liver disease, which is uncommon in beta-oxidation defects, was found in 2 patients. One patient had peripheral neuropathy, and 6 had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. Radiologically, there was bilateral periventricular or focal cortical lesions in 3 patients and brain atrophy in 1. Only 1 patient, who had dietary treatment for 9 years, was alive at the age of 14 years; all others died before they were 2 years of age. The experience indicated the importance of recognizing the clinical features of LCHAD deficiency for the early institution of dietary management, which can alter the otherwise invariably poor prognosis.
Ibdah et al. (1999) reported a patient who presented at 2 months of age with generalized tonic-clonic seizure due to an acute infantile hypocalcemia and vitamin D deficiency. He also had occult, unexplained cholestatic liver disease and impairment of 25-hydroxylation of vitamin D secondary to hepatic steatosis. Sudden unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the E474Q mutation. The mother had preeclampsia during the third trimester of her pregnancy. |
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| Gene |
HADHA |
| Chromosomal Location |
2p23 |
| Allelic Variant 2 |
600890.0001; LCHAD DEFICIENCY |
| Identified Mutation |
GLU510GLN; LCHAD DEFICIENCY WITH MATERNAL ACUTE FATTY LIVER OF PREGNANCY, INCLUDED
HADHA, GLU510GLN [dbSNP:rs137852769] [ClinVar]
Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) had designated the mutation GLU474GLN (E474Q) based on numbering of the mature protein.
IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution, in approximately 87% of the chromosomes in patients with LCHAD deficiency (609016).
Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase to determine the molecular basis of LCHAD deficiency in 3 families in which children presented with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mother had acute fatty liver and associated severe complications during pregnancy. The analysis in 2 affected children demonstrated homozygosity for the E474Q mutation. The third child was compound heterozygous for E474Q and Q342X (600890.0002).
IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q mutation in genomic DNA. Functional expression studies in S. cerevisiae showed that the mutation is directly responsible for the loss of LCHAD activity.
Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency due to a homozygous E474Q mutation. The patients had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Recurrent metabolic crises had occurred in 7 patients; the other 6 had a steadily progressive course. Cholestatic liver disease, which is uncommon in beta-oxidation defects, was found in 2 patients. One patient had peripheral neuropathy, and 6 had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. Radiologically, there was bilateral periventricular or focal cortical lesions in 3 patients and brain atrophy in 1. Only 1 patient, who had dietary treatment for 9 years, was alive at the age of 14 years; all others died before they were 2 years of age. The experience indicated the importance of recognizing the clinical features of LCHAD deficiency for the early institution of dietary management, which can alter the otherwise invariably poor prognosis.
Ibdah et al. (1999) reported a patient who presented at 2 months of age with generalized tonic-clonic seizure due to an acute infantile hypocalcemia and vitamin D deficiency. He also had occult, unexplained cholestatic liver disease and impairment of 25-hydroxylation of vitamin D secondary to hepatic steatosis. Sudden unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the E474Q mutation. The mother had preeclampsia during the third trimester of her pregnancy. |
| Remarks |
Clinically affected; pregnancy complicated by maternal HELLP syndrome; subject born at 37 weeks gestation; hypothermia; hypoglycemia; LCHAD = 8.5 (normal 57.3 +/- 14.9); donor subject is homozygous for a G>C transversion at nucleotide 1528 in exon 15 of the HADHA gene [1528G>C] resulting in a substitution of glutamine for glutamic acid at codon 510 [GLU510GLN (E510Q)]. |
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