Premium
Whole‐exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D ‐2‐hydroxyglutaric aciduria (MC‐HGA)
Author(s) -
Vissers Lisenka E.L.M.,
Fano Virginia,
Martinelli Diego,
CamposXavier Belinda,
Barbuti Domenico,
Cho TaeJoon,
Dursun Ahmet,
Kim Ok Hwa,
Lee Sun Hee,
Timpani Giuseppina,
Nishimura Gen,
Unger Sheila,
Sass Jörn Oliver,
Veltman Joris A.,
Brunner Han G.,
Bonafé Luisa,
DionisiVici Carlo,
SupertiFurga Andrea
Publication year - 2011
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.34325
Subject(s) - exome sequencing , somatic cell , isocitrate dehydrogenase , germline mutation , idh1 , mutation , biology , microbiology and biotechnology , genetics , chemistry , biochemistry , enzyme , gene
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. © 2011 Wiley Periodicals, Inc.