[
Mol Genet Metab,
2007]
3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive genetic disorder that affects ketogenesis and l-leucine catabolism, which generally appears during the first year of life. Patients with HL deficiency have a reduced capacity to synthesize ketone bodies. The disease is caused by lethal mutations in the HL gene (HMGCL). To date, up to 30 variant alleles (28 mutations and 2 SNPs) in 93 patients have been reported, with a recognizable population-specific mutational spectrum. This disorder is frequent in Saudi Arabia and the Iberian Peninsula (Portugal and Spain), where two mutations (122G>A and 109G>A) have been identified in 87% and 94% of the cases, respectively. In most countries a few patients have a high level of allelic heterogeneity. The mutations are distributed along the gene sequences, although some clustering was observed in exon 2, conforming a possible hot spot. Recently, the crystal structures of the human and two bacterial HL have been published. These experimentally obtained structures confirmed the overall architecture, previously predicted by our group and others using bioinformatic approaches, which shows the (betaalpha)8-barrel structure of the enzyme. In addition, the crystals confirmed the presence of an additional COOH domain containing important structures and residues for enzyme functionality and oligomerization processes. Here, we review all HMGCL mis-sense mutations identified to date, and their implication in enzyme structure and function is discussed. We found that genotype-phenotype correlations are difficult to establish because the evolution of the disease seems more related to the causes of hypoglycaemia (fasting or acute illness) than to a particular genotype.
[
Studies of History & Philosophy of Science,
1998]
In 1963, just a year after the researchers of the Medical Research Council (MRC) Unit of Molecular Biology in Cambridge, joined by some other research groups, has moved from various scattered and makeshift buildings in the courtyard of the Physics Department to a lavishly funded four-storey laboratory, B. Lush, the Principal Medical Officer of the MRC, came to inquire about their plans for future expansion. He indicated that the MRC wished to build the laboratory up to what the principal researchers considered its 'final size' until their retirement, which meant planning ahead for at least 15 years. This surprising move was doubtless prompted by the recent award of the Nobel Prize to three members of the laboratory, Max Perutz, John Kendrew and Francis Crick, for their work on the molecular structure of proteins and nucleic acids. The triple award had propelled the new Laboratory of Molecular Biology into the limelight, and the MRC was interested in securing optimal research conditions for this prestigious group of researchers.