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Projects. Life and Earth Sciences

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

Lead Researcher:
María del Pilar Rodríguez Pombo

Research Centre:
Universidad Autónoma de Madrid.

Synopsis: 

María del Pilar Rodríguez PomboKnowledge 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.


Scientific production
1 article published in Journals


María del Pilar Rodríguez Pombo

María del Pilar Rodríguez Pombo has a Doctorate in Biology from the Autonomous University, Madrid (UAM) and is Tenured Professor in the Molecular Biology Department of the said university.

She was visiting professor in the Department of Endocrinology and Metabolism of the School of Medicine of the University of Stanford, USA (1991-1992), and contracted professor in the Autonomous University, Madrid from 1984.

During these years her research has centred on the study of the molecular bases of several hereditary metabolic diseases, including organic acidaemias such as Propionic Acidaemia; amino acid pathologies such as Maple Syrup Urine; and defects in connection with energy metabolism, such as Cerebral Creatinine Syndrome. She has published more than 40 articles in recognised scientific journals and has taken part in a total of 21 research projects in public or private programmes, as Principal Investigator in two of them.

She currently combines her teaching work as professor of Biochemistry and Molecular Biology in the UAM, and research work into the Molecular Bases of Pathology, with her work as the head of genetic diagnosis for Hereditary Metabolic Diseases in the Molecular Diseases Diagnostic Centre (CEDEM). She is also a member of unit U746 of the Centre for Networked Biomedical Research into Rare Diseases (CIBERER).


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