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Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA).
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2011 Nov; Vol. 155A (11), pp. 2609-16. - Publication Year :
- 2011
-
Abstract
- We used exome sequencing of blood DNA in four unrelated patients to identify the genetic basis of metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA), a rare entity comprising severe chondrodysplasia, organic aciduria, and variable cerebral involvement. No evidence for recessive mutations was found; instead, two patients showed mutations in IDH1 predicting p.R132H and p.R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient, and in blood and saliva (but not in fibroblast) DNA in the other patient. Mutations at codon 132 of IDH1 change the enzymatic specificity of the cytoplasmic isocitrate dehydrogenase enzyme. They result in increased D-2-hydroxy-glutarate production, α-ketoglutarate depletion, activation of HIF-1α (a key regulator of chondrocyte proliferation at the growth plate), and reduction of N-acetyl-aspartyl-glutamate level in glial cells. Thus, somatic mutations in IDH1 may explain all features of MC-HGA, including sporadic occurrence, metaphyseal disorganization, and chondromatosis, urinary excretion of D-2-hydroxy-glutaric acid, and reduced cerebral myelinization.<br /> (Copyright © 2011 Wiley Periodicals, Inc.)
- Subjects :
- Brain Diseases, Metabolic, Inborn blood
Brain Diseases, Metabolic, Inborn enzymology
Brain Diseases, Metabolic, Inborn pathology
Brain Diseases, Metabolic, Inborn urine
Chondromatosis blood
Chondromatosis enzymology
Chondromatosis pathology
DNA Mutational Analysis methods
Exome
Female
Genetic Association Studies methods
Genome, Human
Genotype
Glutarates urine
Humans
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Infant
Isocitrate Dehydrogenase blood
Ketoglutaric Acids metabolism
Male
Mutation
Saliva chemistry
Substrate Specificity
Brain Diseases, Metabolic, Inborn genetics
Chondromatosis genetics
Isocitrate Dehydrogenase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 155A
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 22025298
- Full Text :
- https://doi.org/10.1002/ajmg.a.34325