New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations
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- 作者：M¨®nica Ramos ; Sebasti¨¢n Menao ; Mar¨ªa Arnedo ; Beatriz Puisac ; Mar¨ªa Concepci¨®n Gil-Rodr¨ªguez ; Mar¨ªa Esperanza Teresa-Rodrigo ; Mar¨ªa Hern¨¢ndez-Marcos ; Germaine Pierre ; Uma Ramaswami ; Carolina Baquero-Montoya ; Gloria Bueno ; Cesar Casale ; Fausto G. Hegardt ; Paulino G¨®mez-Puertas ; Juan Pi¨¦
- 关键词：Mitochondrial HMG-CoA synthase deficiency ; Mutations ; Ketone bodies
- 刊名：European Journal of Medical Genetics
- 出版年：2013
- 出版时间：August, 2013
- 年：2013
- 卷：56
- 期：8
- 页码：411-415
- 全文大小：804 K
文摘
Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5 % . This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X).