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, ?-ketoglutarate depletion, activation of HIF-1? (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.

Yazar Vissers L.E.M.
Fano V.
Martinelli D.
Campos-Xavier B.
Barbuti D.
Cho T.-J.
Dursun A.
Yayın Türü Article
Tek Biçim Adres https://hdl.handle.net/20.500.12628/8546
Tek Biçim Adres 10.1002/ajmg.a.34325
Konu Başlıkları D-2-hydroxyglutaric acidura
Isocitrate dehydrogenase
Metaphyseal chondromatosis
Mosaicism
Somatic mutation
Whole-genome sequencing
Koleksiyonlar Araştırma Çıktıları | WoS | Scopus | TR-Dizin | PubMed | SOBİAD
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Dergi Adı American Journal of Medical Genetics, Part A
Dergi Cilt Bilgisi 155
Dergi Sayısı 11
Sayfalar 2609 - 2616
Yayın Yılı 2011
Eser Adı
[dc.title]
Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)
Yazar
[dc.contributor.author]
Vissers L.E.M.
Yazar
[dc.contributor.author]
Fano V.
Yazar
[dc.contributor.author]
Martinelli D.
Yazar
[dc.contributor.author]
Campos-Xavier B.
Yazar
[dc.contributor.author]
Barbuti D.
Yazar
[dc.contributor.author]
Cho T.-J.
Yazar
[dc.contributor.author]
Dursun A.
Yayın Yılı
[dc.date.issued]
2011
Yayın Türü
[dc.type]
article
Özet
[dc.description.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, ?-ketoglutarate depletion, activation of HIF-1? (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.
Kayıt Giriş Tarihi
[dc.date.accessioned]
2019-12-23
Açık Erişim Tarihi
[dc.date.available]
2019-12-23
Yayın Dili
[dc.language.iso]
eng
Konu Başlıkları
[dc.subject]
D-2-hydroxyglutaric acidura
Konu Başlıkları
[dc.subject]
Isocitrate dehydrogenase
Konu Başlıkları
[dc.subject]
Metaphyseal chondromatosis
Konu Başlıkları
[dc.subject]
Mosaicism
Konu Başlıkları
[dc.subject]
Somatic mutation
Konu Başlıkları
[dc.subject]
Whole-genome sequencing
Haklar
[dc.rights]
info:eu-repo/semantics/closedAccess
ISSN
[dc.identifier.issn]
1552-4825
İlk Sayfa Sayısı
[dc.identifier.startpage]
2609
Son Sayfa Sayısı
[dc.identifier.endpage]
2616
Dergi Adı
[dc.relation.journal]
American Journal of Medical Genetics, Part A
Dergi Sayısı
[dc.identifier.issue]
11
Dergi Cilt Bilgisi
[dc.identifier.volume]
155
Tek Biçim Adres
[dc.identifier.uri]
https://dx.doi.org/10.1002/ajmg.a.34325
Tek Biçim Adres
[dc.identifier.uri]
https://hdl.handle.net/20.500.12628/8546
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09.12.2022 tarihinden bu yana
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mutations chondromatosis cerebral somatic excretion urinary metaphyseal sequencing patients patient D-2-hydroxy-glutaric activation regulator change enzymatic HIF-1? specificity dehydrogenase chondrocyte ?-ketoglutarate enzyme production D-2-hydroxy-glutarate increased result cytoplasmic isocitrate depletion proliferation including Periodicals myelinization reduced disorganization occurrence
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