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Tytuł pozycji:

Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene

Tytuł :
Thirteen new patients with guanidinoacetate methyltransferase deficiency and functional characterization of nineteen novel missense variants in the GAMT gene
Autorzy :
Mercimek-Mahmutoglu, S.
Ndika, J.
Kanhai, W.
Villemeur, T. B.
Cheillan, David
Christensen, E.
Dorison, N.
Hannig, V.
Hendriks, Y.
Hofstede, F. C.
Lion-Francois, L.
Lund, A. M.
Mundy, H.
Pitelet, G.
Raspall-Chaure, M.
Scott-Schwoerer, J. A.
Szakszon, K.
Valayannopoulos, V.
Williams, M.
Salomons, G. S.
Pokaż więcej
Temat :
Adolescent
Adult
Female
Humans
Male
Young Adult
Child
Preschool
Surveys and Questionnaires
Fibroblasts/enzymology
Genetic Predisposition to Disease
Genetic Variation
Guanidinoacetate N-Methyltransferase/*deficiency/genetics/metabolism
Language Development Disorders/*genetics/*pathology
Movement Disorders/*congenital/genetics/pathology
Mutation
Missense
[SDV]Life Sciences [q-bio]
Źródło :
Human Mutation, Wiley, 2014, 35 (4), pp.462-9. ⟨10.1002/humu.22511⟩
Wydawca :
Wiley, 2014.
Rok publikacji :
2014
Kolekcja :
HAL-Pasteur
Język :
English
ISSN :
1059-7794
1098-1004
DOI :
10.1002/humu.22511
Numer akcesji :
edsair.od......2100..7f9aa0dc0bfd55c2cb085370f671fed5
International audience; Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C\textgreaterA (p.Pro8Thr) and c.79T\textgreaterC (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.

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