Trends in Genetics
Volume 19, Issue 5, May 2003, Pages 257-262
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Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear–mitochondrial interaction

https://doi.org/10.1016/S0168-9525(03)00072-6Get rights and content

Abstract

Here we define a category of human, maternally inherited disorders that are characterized by a homoplasmic mtDNA pathogenic mutation with variable penetrance and a stereotypical clinical expression, usually restricted to a single tissue. Examples of such disorders include Leber's hereditary optic neuropathy, mitochondrial non-syndromic sensorineural hearing loss, and a form of mitochondrial hypertrophic cardiomyopathy. The mtDNA mutation is necessary, but not sufficient to induce the pathology, and multiple lines of evidence suggest a two-locus genetic model involving a primary mitochondrial mutation and a nuclear modifier. The nuclear modifier does not induce any pathology per se, but it contributes to the pathogenic effect of the mitochondrial mutation. The nuclear modifier could be a common functional polymorphism in a tissue-specific protein, possibly with mitochondrial location.

Section snippets

The exceptions to the rules

As always, there are exceptions to these rules. Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by selective death of retinal ganglion cells followed by optic nerve atrophy [4]. Most cases of the disease are associated with one of three mtDNA point mutations (G11778A, G3460A, and T14484C) affecting genes encoding complex I (NADH:ubiquinone oxidoreductase) subunits, and currently regarded as pathogenic. A few additional, but infrequent mutations, also

The two-locus hypothesis: is a nuclear modifier gene involved?

In all three of the above conditions, the homoplasmic mtDNA mutation is not sufficient to account for the variable penetrance, implying that there must be some modifier involved. The first plausible modifier is the mtDNA background itself, and this has been investigated in both LHON and SNHL. In LHON, high versus low-penetrance pedigree branches were not associated with additional mtDNA mutations [5], but haplotype and phylogenetic analysis of mtDNA revealed an association of the G11778A and

Candidate genes: where to look

According to the two-locus model, and assuming that the mitochondrial mutation is the primary pathogenic event based on maternal inheritance of these disorders, the nuclear modifier probably does not induce any pathology per se, or it might manifest only subclinically. Thus, most probably the nuclear modifier involves one or more common functional polymorphisms, not ethnically restricted, considering the worldwide distribution of at least LHON and 1555-SNHL.

In LHON complex I dysfunction is

Candidate genes: how to find them

The identification of potential candidates using current knowledge of the pathophysiology of these disorders, or by analogy with other known examples of multigene disease control, is not always successful. Also, conventional genetic approaches such as linkage analysis, might not be informative when there are many factors contributing to the disease, possibly a mixture of low-grade genetic effects and environmental factors. However, two potentially powerful tools are now available to circumvent

Conclusions

We have identified a distinct subgroup of mitochondrial disorders having the following characteristics:

  • the disease is maternally inherited;

  • the clinical expression is stereotypical, mainly restricted to a single tissue;

  • a homoplasmic mutation in the mitochondrial genome is the primary pathogenic event, but is not sufficient to induce the disease;

  • this mutation can be in a protein-coding gene, a tRNA or an rRNA gene, and is thus heterogeneous in its pathophysiology;

  • in some disorders, there is a

Acknowledgements

We thank Eric Schon (Columbia University, New York, USA) and Alfredo Sadun (USC, Los Angeles, USA) for related discussions. Research on LHON is supported by Telethon-Italy (V.C., GGP02323) and by ‘Fondazione Gino Galletti’. Research on 1555-related deafness is supported by Telethon-Italy (C.G., 3031b).

Glossary

Glossary

Cybrid cells (cybrids):
Cancer-derived immortalized cells that are depleted of their own mtDNA by long-term exposure to ethidium bromide (ρ0 cells), and have been repopulated with exogenous mitochondria carrying a specific mtDNA mutation by fusion with patient-derived enucleated cells (cytoplasts).
Haplogroup J:
An mtDNA haplogroup is a group of mtDNAs that is defined by a unique set of variants acquired from the same ancient common female ancestor. Haplogroup J is specific of European and Near

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