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Molecular basis of 3-hydroxy-3-methylglutaric aciduria

Base molecular de la aciduria 3-hidroxi-3-metilglutárica

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Abstract

3-Hydroxy-3-methylglutaric aciduria is a human autosomal recessive metabolic disorder that usually appears within the first year of life. The causes of this aciduria are lethal mutations in the gene encoding for 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL). HL is a mitochondrial matrix enzyme that catalyzes the last step of ketogenesis and leucine catabolism. This gene has been mapped to chromosome 1 at locus 1pter-p33 and its genomic organisation comprises 9 exons whose sizes vary between 64–678 bp. The human cDNA sequence was reported in 1993 with the first genetic study of two Acadian-French Canadian siblings. To date, 24 mutations in 36 patients have been described; most of them are single-base substitutions causing amino acid replacements and a variety of splicing defects. In the population studied two mutations appear predominant: g.122G®A (8 patients and 15 alleles) frequent in Saudi Arabia, and g.109G®T (6 patients and 12 alleles), prevalent in Spain. At least seven mutations are clustered in the second half of exon 2 affecting aminoacids E37, R41 and D42 and conforming a possible hot spot. The genotype-phenotype correlation is difficult to establish since the probands received different treatments, and the onset of an acute episode frequently depends on external factors such as fasting or acute illness.

Resumen

La aciduria 3-hidroxi-3-metilglutárica es una metabolopatía autosómica recesiva que suele manifestarse durante el primer año de vida. Las causas de la aciduria son mutaciones letales en el gen que codifica para la 3-hidroxi-3-metilglutaril coenzima A liasa (HL). La HL es una enzima de la matriz mitocondrial que cataliza la última etapa de la cetogénesis y del catabolismo de la leucina. Su gen ha sido localizado en el cromosoma 1 en el locus 1pter-p33 y la organización genómica comprende 9 exones cuyos tamaños oscilan entre 64 y 678 bp. La secuencia del cDNA fue publicada en 1993 acompañada del primer estudio sobre las bases moleculares de la aciduria 3-hidroxi-3-metil glutárica en dos hermanos canadienses de origen francés-acadiano. En la actualidad, se han descrito 24 mutaciones diferentes en 36 pacientes distintos, la mayoría han consistido en sustituciones de una base produciendo cambios de un aminoácido y defectos en la maduración del mRNA. En la población estudiada aparecen dos mutaciones predominantes: La g.122G®A (8 pacientes y 15 alelos) muy frecuente en Arabia Saudita, y la g.109G®T (6 pacientes y 12 alelos), prevalente en España. Al menos siete mutaciones se concentran en la segunda mitad del exon 2 afectando a los aminoácidos E37, R41, y D42 y conformando una posible zona de mutación. Las correlaciones genotipo-fenotipo son difíciles de establecer por el diferente tratamiento de los pacientes y porque el comienzo del episodio agudo depende frecuentemente de causas externas tales como el ayuno o una enfermedad infecciosa.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, Zaragoza, Spain

    J. Pie & B. Puisac

  2. Department of Biochemistry and Molecular Biology, School of Health Sciences, International University of Catalonian, Catalonian, Spain

    N. Casals

  3. Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Avda. Diagonal 643, 08028, Barcelona, Spain

    F. G. Hegardt

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  1. J. Pie
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Correspondence to F. G. Hegardt.

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Pie, J., Casals, N., Puisac, B. et al. Molecular basis of 3-hydroxy-3-methylglutaric aciduria. J Physiol Biochem 59, 311–321 (2003). https://doi.org/10.1007/BF03179889

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