Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA).
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.
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen, Netherlands.
Lisenka E L M
LE
Vissers
Virginia
V
Fano
Diego
D
Martinelli
Belinda
B
Campos-Xavier
Domenico
D
Barbuti
Tae-Joon
TJ
Cho
Ahmet
A
Dursun
Ok Hwa
OH
Kim
Sun Hee
SH
Lee
Giuseppina
G
Timpani
Gen
G
Nishimura
Sheila
S
Unger
Jörn Oliver
JO
Sass
Joris A
JA
Veltman
Han G
HG
Brunner
Luisa
L
Bonafé
Carlo
C
Dionisi-Vici
Andrea
A
Superti-Furga
D020739:Brain Diseases, Metabolic, Inborn / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000652:urine; D018210:Chondromatosis / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D015894:Genome, Human; D005838:Genotype; D005977:Glutarates / Q000652:urine; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007223:Infant; D007521:Isocitrate Dehydrogenase / Q000097:blood / Q000235:genetics*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D009154:Mutation; D012463:Saliva / Q000737:chemistry; D013379:Substrate Specificity
D005977:Glutarates; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human