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Hereditary metabolic diseases: searching for new genes that cause diseases and research into new therapeutic strategies

16th national competition for scientific and technical research

Rare diseases

Senior Researcher : Mª del Pilar Rodríguez Pombo

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Research Centre or Institution : Universidad Autónoma de Madrid.


Knowledge about the genes and mutations causing pathologies is, nowadays, a fundamental element in research into hereditary metabolic diseases. In this first phase of working, and based on the principle that it is possible to phenotype mutations, a search is under way for the gene responsible for the pathology of a patient diagnosed Maple Syrup Urine Disease (MSUD), for which to date no pathogenic mutations had been identified in any of the genes involved in the disease. MSUD is a recessive autosomal disease caused by a defect in the activity of the multi-enzymatic mitochondrial branched chain α‑keto acid dehydrogenase complex (BCKDH), and it has a major impact on the working of the nervous system.

The prior detection of a complete loss of heterozygosity in chromosome four of our patient, using a genotyped array which made it possible to trace more than 600,000 polymorphic changes (SNPs) located along the whole chromosomal DNA, permitted the selection of the PPM1K gene, which codes for the PP2Cm phosphatase which is implicated in the dephosphorylation and subsequent activation of the BCKDH complex, as the best candidate to be responsible for this pathology. Conventional sequencing of this gene identified mutation c.417_418delTA in homozygosis but absent in 300 healthy Caucasian alleles. The final proof of the relationship between the genetic defect and the pathology required functional analysis of the change identified at several levels, including: its effect on the stability of the PP2Cm mutant protein, using intracellular co-localisation analysis of the normal and mutant proteins, together with studies of expression by western blot; and the recovery of BCKDH activity which was deficient in fibroblasts of the patient following the ectopic expression of normal human PP2Cm. This study identified the first case of a MSUD patient with a defect in the regulation of the BCKDH complex.

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