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Milano www.mitopedia.org Istituto Nazionale Neurologico C. Besta Mutazioni primarie del mtDNA Massimo Zeviani IUSS, Medicina Mitocondriale.

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Presentation on theme: "Milano www.mitopedia.org Istituto Nazionale Neurologico C. Besta Mutazioni primarie del mtDNA Massimo Zeviani IUSS, Medicina Mitocondriale."— Presentation transcript:

1 Milano Istituto Nazionale Neurologico C. Besta Mutazioni primarie del mtDNA Massimo Zeviani IUSS, Medicina Mitocondriale

2 mtDNA mutations Heteroplasmic mutations Homoplasmic mutations Single-Nucleotide Polymorphisms

3 homoplasmic mother her offspring (usually) healthy (usually) sick Mutation is necessary but not sufficient to produce the disease phenotype Homoplasmic point mutation eg, LHON mitochondrial bottleneck mitochondrial proliferation her oogonia

4 the A1555G affects the aminoglycoside binding site of 12S rRNA Secondary structure of decoding site of small ribosomal RNAs. The A site of E. coli 16 S rRNA oligonucleotide showing the DMS footprints, observed in the presence of the aminoglycosides neomycin and paromomycin, is marked with a dot (A). The corresponding region of S. cerevisiae mt-15S rRNA and human mt-12S rRNA is shown as the wild type version (B and E) and in the version containing the PR454 (C) and A1555G mutation (F), respectively.

5 modifier loci/genes

6 Sequence alignment of human Mto1p with its homologs MTO1 COX1 overlap

7 Lebers Hereditary Optic Neuropathy (LHON) Leber, T. : Ueber hereditaere und congenital angelegte Sehnervenleiden. Graefes Arch. Ophthal. 17: , 1871.

8 Homoplasmic point mutations e.g. Lebers Hereditary Optic Neuropathy 11778G->A blind healthy

9 mutant wt Homoplasmic point mutations e.g. Lebers Hereditary Optic Neuropathy 11778G->A

10 LHON/14484C 26% LHON/11778A 58% LHON/3460A 16%

11 Hudson et al, Am J Hum Genet 2007

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13 Am J Hum Genet 2007

14 Hudson et al, Am J Hum Genet 2007

15 SNHL/1555G LHON/14482G/A LHON/14485C LHON14495G LHON/14568T LHON/11778A LHON/3460A LHON/4171A LHON/10663C Homoplasmic mutations syndromic SNHL/7472insC aminoglycoside-induced SNHL/delT961 neonatal death- Leigh s./16427T SNHL/7445C SNHL/7510C SNHL/7511C MIHC/9997C MIHC/4300G Leigh s./9537insC Encephalopathy obesity/4290C hypertension hyperchol. hypoMg ++ /4291C

16 Published online: 22 January 2002, doi: /ng819 volume 30 no. 2 pp Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation Robert McFarland1, Kim M. Clark1, Andrew A.M. Morris2, Robert W. Taylor1, Sheila Macphail3, Robert N. Lightowlers1 & Douglass M. Turnbull1 C1624T 230 bp 201 bp 154 bp 47 bp II-1 muscle II-1 blood I-2 blood III-6 buccal III-9 placenta control 1 blood undigested control 2 cardiac III-10 blood III-10muscle III-10cardiac undigested Rsa I Digestion 21h pH Alive Leigh s. 85h pH 30h pH 26h pH 2h pH 12h pH Control motherPatient III-10 Heteroplasmic tRNA mutation Cytochrome c oxidase activity Skeletal muscleCardiac mitochondria

17 Healthy Ataxia, dystonia, tetraparesis, optic atrophy, DM, obesity Same as older sister. Deceased at 16 yrs. Deceased at 1 yr. Necrotizing encephalopathy Activities in the living proband (fibroblasts) CI/CS CIV/CS P P C C

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19 control complex I complex IV Respiratory Chain Activities in Cybrids nmol/min/mg protein p1 p2 p3 CI/CS CIV/CS P1: mother P2, P3: patients I-2 II-2 C 2D-BNE on complex IV WT IV-1 WT II-1 ND5 COI ND4 cyt b ND2 ND1 COIII COII ATP6 ND6 ND3 ND4L ATP8 Mito-specific protein synthesis

20 T4291C Familial hypomagnesemia, hypertension, and hypercholesterolemia

21 LHON/14484C haplo J 100% LHON/11778A haplo J p.02 LHON/3460A haplo K p 2.3x10 -3 haplo J-> cyt. b L236I haplo J1c-> cyt. b F18L haplo J2b-> cyt. b D171N cyt. b V356M haplo K-> cyt. b F18L Increased penetrance of LHON mutations in haplogroups J and K

22 mtDNA mutations Heteroplasmic mutations Homoplasmic mutations Single-Nucleotide Polymorphisms

23 What is the impact of mildly pathogenic mtDNA mutations or haplotypes? - haplogroup distribution during human migrations - haplogroup J vs. H in LHON - haplogroup H vs. T in asthenozoospermia - haplogroup K vs. H in Parkinson's Disease mtDNA haplotypes

24 Gene products present in mammalian mitochondria

25 Genetic classification of OXPHOS disease mutations Defects of Mitochondrial DNA Protein synthesis genes (rRNAs, tRNAs) Protein-encoding OXPHOS subunit genes Large deletions Nuclear DNA mutations Protein-encoding OXPHOS subunit genes Genes encoding OXPHOS assembly factors Genes encoding factors affecting mtDNA maintenance Mitochondrial protein synthesis genes Genes encoding biosynthetic enzymes for lipids or cofactors Genes involved in mitochondrial biogenesis

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40 Chemiosomosis Chemiosmosis is the name given to the generation of ATP from a proton gradient. It occurs in all living things

41 Chemiosomosis photosynthetic archaea

42 Chemiosomosis purple proteobacteria

43 Chemiosomosis mitochondria

44 Chemiosomosis Chloroplasts


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