My researches during the DIMET project have been focused on the discovery of new genes responsible for mitochondrial disorders and the characterization of their role. Recent epidemiological studies show that mitochondrial disorders have an incidence of 1:5000. These disorders are very heterogeneous and hence the diagnosis is difficult. Moreover mitochondrial dysfunctions are now clearly related to a wide range of disease conditions (i.e. neurodegeneration and cancer). The majority of the inherited mitochondrial disorders, especially those with onset in infancy or childhood, are due to nuclear genes encoding proteins targeted to mitochondria. While identification of mutations in mitochondrial DNA has become relatively easy thank to the feasibility to perform the complete sequence analysis of mtDNA, the analysis of genomic DNA is more complicate and therefore the number of nuclear genes associated with mitochondrial diseases is still small. Genome-wide analysis in families with autosomal recessive mitochondrial disorders could help to identify a genomic region to be further investigated. However, about one half/one third of the components of the mitochondrial proteome have yet to be identified, and this lack of information makes the search of candidate genes more difficult. By linkage analysis or homozygosity mapping and prioritization of candidate genes, I studied subjects from multiconsanguineos families characterized by clinical pictures compatible with mitochondrial disorders. In chapter 2, there is the report regarding the discovery of a nonsense mutation in two brothers displaying asymmetric brain atrophy, psychomotor regression and severe complex IV deficiency. The mutated gene codes for a mitochondrial predicted kinase that may have a role in apoptosis. Using the same procedure, I take part in a project, which leads to the identification of the first assembly factor for complex II of the OXPHOS system (Chapter 3). Two different mutations were found in two pedigrees, with affected children characterized by acute psychomotor regression followed by spastic quadriparesis and/or dystonia. The pathogenic role of the mutations was confirmed in cellular and yeast models. Finally, in chapter 4, there is the characterization of a protein, MR-1, already known and responsible for a movement disorder (PNKD, Paroxysmal non kinesigenic Dyskinesia). The mutant isoforms were erroneously localized into cytosol or membranes, whereas I demonstrated that they are mitochondrial and that the mutations reported so far in PNKD patients (and a new mutation identify in our study) are in the mitochondrial targeting signal (MTS). Hence PNKD could be considered a mitochondrial disease, due to a novel mechanism based on a deleterious action of the MTS.

(2009). Identification and characterization of nuclear genes responsible for human mitochondrial disorders: fastkd2, responsible for a neurological disease associated with cox defiency and sdhaf1, encoding a complex II assembly, mutated in SDH-defective leukoencephalopaty. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2009).

Identification and characterization of nuclear genes responsible for human mitochondrial disorders: fastkd2, responsible for a neurological disease associated with cox defiency and sdhaf1, encoding a complex II assembly, mutated in SDH-defective leukoencephalopaty

GHEZZI, DANIELE
2009-11-27

Abstract

My researches during the DIMET project have been focused on the discovery of new genes responsible for mitochondrial disorders and the characterization of their role. Recent epidemiological studies show that mitochondrial disorders have an incidence of 1:5000. These disorders are very heterogeneous and hence the diagnosis is difficult. Moreover mitochondrial dysfunctions are now clearly related to a wide range of disease conditions (i.e. neurodegeneration and cancer). The majority of the inherited mitochondrial disorders, especially those with onset in infancy or childhood, are due to nuclear genes encoding proteins targeted to mitochondria. While identification of mutations in mitochondrial DNA has become relatively easy thank to the feasibility to perform the complete sequence analysis of mtDNA, the analysis of genomic DNA is more complicate and therefore the number of nuclear genes associated with mitochondrial diseases is still small. Genome-wide analysis in families with autosomal recessive mitochondrial disorders could help to identify a genomic region to be further investigated. However, about one half/one third of the components of the mitochondrial proteome have yet to be identified, and this lack of information makes the search of candidate genes more difficult. By linkage analysis or homozygosity mapping and prioritization of candidate genes, I studied subjects from multiconsanguineos families characterized by clinical pictures compatible with mitochondrial disorders. In chapter 2, there is the report regarding the discovery of a nonsense mutation in two brothers displaying asymmetric brain atrophy, psychomotor regression and severe complex IV deficiency. The mutated gene codes for a mitochondrial predicted kinase that may have a role in apoptosis. Using the same procedure, I take part in a project, which leads to the identification of the first assembly factor for complex II of the OXPHOS system (Chapter 3). Two different mutations were found in two pedigrees, with affected children characterized by acute psychomotor regression followed by spastic quadriparesis and/or dystonia. The pathogenic role of the mutations was confirmed in cellular and yeast models. Finally, in chapter 4, there is the characterization of a protein, MR-1, already known and responsible for a movement disorder (PNKD, Paroxysmal non kinesigenic Dyskinesia). The mutant isoforms were erroneously localized into cytosol or membranes, whereas I demonstrated that they are mitochondrial and that the mutations reported so far in PNKD patients (and a new mutation identify in our study) are in the mitochondrial targeting signal (MTS). Hence PNKD could be considered a mitochondrial disease, due to a novel mechanism based on a deleterious action of the MTS.
TIRANTI, VALERIA
mitochondrial disease, gene discovery
MED/03 - GENETICA MEDICA
English
Scuola di Dottorato in Medicina Traslazionale e Molecolare
MEDICINA TRASLAZIONALE E MOLECOLARE (DIMET) - 45R
22
2008/2009
(2009). Identification and characterization of nuclear genes responsible for human mitochondrial disorders: fastkd2, responsible for a neurological disease associated with cox defiency and sdhaf1, encoding a complex II assembly, mutated in SDH-defective leukoencephalopaty. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2009).
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/7657
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