MtDNA Depletion with Variable Tissue Expression: a Novel Genetic Abnormality in Mitochondrial Diseases

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1991 Mar 1

PMID 1998336

Citations 138

Authors

C T Moraes

S Shanske

H J Tritschler

J R Aprille

F Andreetta

E Bonilla

E A Schon

S DiMauro

Affiliations

Soon will be listed here.

Abstract

We studied two related infants with a fatal mitochondrial disease, affecting muscle in one and liver in the other. Quantitative analysis revealed a severe depletion of mtDNA in affected tissues. This genetic abnormality was also observed in muscle of an unrelated infant with myopathy and in muscle and kidney of a fourth child with myopathy and nephropathy. Biochemistry, immunohistochemistry, and in situ hybridization showed that the depletion of mtDNA in muscle fibers was correlated with a respiratory chain defect and with lack of mitochondrially translated proteins. Although the differential tissue involvement in these infants suggests mtDNA heteroplasmy, sequence analysis of mtDNA replication origins did not reveal any abnormality that could account for the low copy number.

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References

Zeviani M, Gellera C, Pannacci M, Uziel G, Prelle A, Servidei S . Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies. Ann Neurol. 1990; 28(1):94-7. DOI: 10.1002/ana.410280118. View

Engel W, CUNNINGHAM G . RAPID EXAMINATION OF MUSCLE TISSUE. AN IMPROVED TRICHROME METHOD FOR FRESH-FROZEN BIOPSY SECTIONS. Neurology. 1963; 13:919-23. DOI: 10.1212/wnl.13.11.919. View

PIKO L . Synthesis of macromolecules in early mouse embryos cultured in vitro: RNA, DNA, and a polysaccharide component. Dev Biol. 1970; 21(1):257-9. DOI: 10.1016/0012-1606(70)90071-0. View

Bross K, Krone W . On the number of ribosomal RNA genes in man. Humangenetik. 1972; 14(2):137-41. DOI: 10.1007/BF00273298. View

Schmickel R . Quantitation of human ribosomal DNA: hybridization of human DNA with ribosomal RNA for quantitation and fractionation. Pediatr Res. 1973; 7(1):5-12. DOI: 10.1203/00006450-197301000-00002. View

Bogenhagen D, Clayton D . The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells. Quantitative isolation of mitochondrial deoxyribonucleic acid. J Biol Chem. 1974; 249(24):7991-5. View

PIKO L, Matsumoto L . Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Dev Biol. 1976; 49(1):1-10. DOI: 10.1016/0012-1606(76)90253-0. View

Young B, Hell A, BIRNIE G . A new estimate of human ribosomal gene number. Biochim Biophys Acta. 1976; 454(3):539-48. DOI: 10.1016/0005-2787(76)90279-3. View

Schmickel R, KNOLLER M . Characterization and localization of the human genes for ribosomal ribonucleic acid. Pediatr Res. 1977; 11(8):929-35. DOI: 10.1203/00006450-197708000-00015. View

10.

Wilson G, Hollar B, Waterson J, Schmickel R . Molecular analysis of cloned human 18S ribosomal DNA segments. Proc Natl Acad Sci U S A. 1978; 75(11):5367-71. PMC: 392964. DOI: 10.1073/pnas.75.11.5367. View

11.

Anderson S, Bankier A, Barrell B, de Bruijn M, Coulson A, Drouin J . Sequence and organization of the human mitochondrial genome. Nature. 1981; 290(5806):457-65. DOI: 10.1038/290457a0. View

12.

Cascio S, Wassarman P . Program of early development in the mammal: synthesis of mitochondrial proteins during oogenesis and early embryogenesis in the mouse. Dev Biol. 1981; 83(1):166-72. DOI: 10.1016/s0012-1606(81)80019-x. View

13.

Bibb M, Van Etten R, Wright C, Walberg M, Clayton D . Sequence and gene organization of mouse mitochondrial DNA. Cell. 1981; 26(2 Pt 2):167-80. DOI: 10.1016/0092-8674(81)90300-7. View

14.

Clayton D . Replication of animal mitochondrial DNA. Cell. 1982; 28(4):693-705. DOI: 10.1016/0092-8674(82)90049-6. View

15.

Anderson S, de Bruijn M, Coulson A, Eperon I, SANGER F, Young I . Complete sequence of bovine mitochondrial DNA. Conserved features of the mammalian mitochondrial genome. J Mol Biol. 1982; 156(4):683-717. DOI: 10.1016/0022-2836(82)90137-1. View

16.

Michaels G, Hauswirth W, Laipis P . Mitochondrial DNA copy number in bovine oocytes and somatic cells. Dev Biol. 1982; 94(1):246-51. DOI: 10.1016/0012-1606(82)90088-4. View

17.

Shmookler Reis R, Goldstein S . Mitochondrial DNA in mortal and immortal human cells. Genome number, integrity, and methylation. J Biol Chem. 1983; 258(15):9078-85. View

18.

Boustany R, Aprille J, Halperin J, Levy H, Delong G . Mitochondrial cytochrome deficiency presenting as a myopathy with hypotonia, external ophthalmoplegia, and lactic acidosis in an infant and as fatal hepatopathy in a second cousin. Ann Neurol. 1983; 14(4):462-70. DOI: 10.1002/ana.410140411. View

19.

Hauswirth W, Clayton D . Length heterogeneity of a conserved displacement-loop sequence in human mitochondrial DNA. Nucleic Acids Res. 1985; 13(22):8093-104. PMC: 322112. DOI: 10.1093/nar/13.22.8093. View

20.

Desjardins P, de Muys J, Morais R . An established avian fibroblast cell line without mitochondrial DNA. Somat Cell Mol Genet. 1986; 12(2):133-9. DOI: 10.1007/BF01560660. View