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New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations.
Eur J Med Genet. 2013 Aug; 56(8):411-5.EJ

Abstract

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).

Authors+Show Affiliations

Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology Physiology, Medical School, University of Zaragoza, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23751782

Citation

Ramos, Mónica, et al. "New Case of Mitochondrial HMG-CoA Synthase Deficiency. Functional Analysis of Eight Mutations." European Journal of Medical Genetics, vol. 56, no. 8, 2013, pp. 411-5.
Ramos M, Menao S, Arnedo M, et al. New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. Eur J Med Genet. 2013;56(8):411-5.
Ramos, M., Menao, S., Arnedo, M., Puisac, B., Gil-Rodríguez, M. C., Teresa-Rodrigo, M. E., Hernández-Marcos, M., Pierre, G., Ramaswami, U., Baquero-Montoya, C., Bueno, G., Casale, C., Hegardt, F. G., Gómez-Puertas, P., & Pié, J. (2013). New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. European Journal of Medical Genetics, 56(8), 411-5. https://doi.org/10.1016/j.ejmg.2013.05.008
Ramos M, et al. New Case of Mitochondrial HMG-CoA Synthase Deficiency. Functional Analysis of Eight Mutations. Eur J Med Genet. 2013;56(8):411-5. PubMed PMID: 23751782.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. AU - Ramos,Mónica, AU - Menao,Sebastián, AU - Arnedo,María, AU - Puisac,Beatriz, AU - Gil-Rodríguez,María Concepción, AU - Teresa-Rodrigo,María Esperanza, AU - Hernández-Marcos,María, AU - Pierre,Germaine, AU - Ramaswami,Uma, AU - Baquero-Montoya,Carolina, AU - Bueno,Gloria, AU - Casale,Cesar, AU - Hegardt,Fausto G, AU - Gómez-Puertas,Paulino, AU - Pié,Juan, Y1 - 2013/06/07/ PY - 2013/01/28/received PY - 2013/05/27/accepted PY - 2013/6/12/entrez PY - 2013/6/12/pubmed PY - 2014/3/7/medline KW - Ketone bodies KW - Mitochondrial HMG-CoA synthase deficiency KW - Mutations SP - 411 EP - 5 JF - European journal of medical genetics JO - Eur J Med Genet VL - 56 IS - 8 N2 - 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). SN - 1878-0849 UR - https://www.unboundmedicine.com/medline/citation/23751782/New_case_of_mitochondrial_HMG_CoA_synthase_deficiency__Functional_analysis_of_eight_mutations_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1769-7212(13)00126-2 DB - PRIME DP - Unbound Medicine ER -