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Ch. 9 - Extranuclear Inheritance
Klug - Concepts of Genetics 12th Edition
Klug12th EditionConcepts of Genetics ISBN: 9780135564776Not the one you use?Change textbook
All textbooksKlug 12th EditionCh. 9 - Extranuclear InheritanceProblem 18b
Chapter 9, Problem 18b

Mutations in mitochondrial DNA appear to be responsible for a number of neurological disorders, including myoclonic epilepsy and ragged-red fiber disease, Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. In each case, the disease phenotype is expressed when the ratio of mutant to wild-type mitochondria exceeds a threshold peculiar to each disease, but usually in the 60 to 95 percent range.
Compared with the vast number of mitochondria in an embryo, the number of mitochondria in an ovum is relatively small. Might such an ooplasmic mitochondrial bottleneck present an opportunity for therapy or cure? Explain.

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1
Understand the concept of mitochondrial inheritance: Mitochondria are inherited maternally, meaning they are passed from the mother to the offspring through the cytoplasm of the ovum. Mutations in mitochondrial DNA (mtDNA) can lead to diseases if the proportion of mutant mitochondria exceeds a certain threshold.
Recognize the mitochondrial bottleneck: During oogenesis (egg development), the number of mitochondria in the developing ovum is reduced significantly, creating a bottleneck. This means that only a small subset of the mother's mitochondria are passed on to the egg, which can lead to variability in the proportion of mutant and wild-type mitochondria in the offspring.
Consider the therapeutic potential of the bottleneck: Since the bottleneck reduces the number of mitochondria, it may provide an opportunity to manipulate the mitochondrial population. For example, techniques like mitochondrial replacement therapy (MRT) could be used to replace mutant mitochondria with healthy ones during this stage.
Explain how this could work: In MRT, healthy mitochondria from a donor egg could be introduced into the ovum, replacing the mutant mitochondria. This would reduce the proportion of mutant mitochondria below the disease threshold, potentially preventing the expression of the disease phenotype in the offspring.
Discuss the implications: While the mitochondrial bottleneck presents a potential opportunity for therapy, ethical, technical, and regulatory considerations must be addressed. Additionally, the success of such therapies would depend on precise control over the mitochondrial population and ensuring the safety of the procedure.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

Mitochondrial DNA and Mutations

Mitochondrial DNA (mtDNA) is distinct from nuclear DNA and is inherited maternally. Mutations in mtDNA can lead to various diseases, particularly affecting energy-intensive tissues like the nervous system. Understanding how these mutations impact mitochondrial function is crucial for grasping the underlying mechanisms of mitochondrial disorders.
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Threshold Effect in Mitochondrial Diseases

The threshold effect refers to the phenomenon where a certain proportion of mutant mitochondria must be present for a disease phenotype to manifest. In mitochondrial disorders, this threshold typically ranges from 60% to 95% mutant mitochondria, meaning that below this level, the wild-type mitochondria can compensate for the dysfunction, preventing disease symptoms.
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Ooplasmic Mitochondrial Bottleneck

The ooplasmic mitochondrial bottleneck is a phenomenon during oocyte development where only a limited number of mitochondria are passed from the mother to the offspring. This bottleneck can create an opportunity for therapeutic interventions, as it may allow for the selection of healthier mitochondria, potentially reducing the transmission of mitochondrial diseases to the next generation.
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Related Practice
Textbook Question

The maternal-effect mutation bicoid (bcd) is recessive. In the absence of the bicoid protein product, embryogenesis is not completed. Consider a cross between a female heterozygous for the bicoid alleles (bcd⁺/bcd⁻) and a male homozygous for the mutation (bcd⁻/bcd⁻).

How is it possible for a male homozygous for the mutation to exist?

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Textbook Question

(a) In humans the mitochondrial genome encodes a low number of proteins, rRNAs, and tRNAs but imports approximately 1100 proteins encoded by the nuclear genome. Yet, with such a small proportion from the mitochondrial genome encoding proteins and RNAs, a disproportionately high number of genetic disorders due to mtDNA mutations have been identified [Bigger, B. et al. (1999)]. What inheritance pattern would you expect in a three-generation pedigree in which the grandfather expresses the initial mtDNA defect? What inheritance pattern would you expect in a three-generation pedigree in which the grandmother expresses the initial mtDNA defect?

(b) Considering the description in part (a) above, how would your pedigrees change if you knew that the mutation that caused the mitochondrial defect was recessive and located in the nuclear genome, was successfully transported into mitochondria, and negated a physiologically important mitochondrial function?

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Textbook Question

Mutations in mitochondrial DNA appear to be responsible for a number of neurological disorders, including myoclonic epilepsy and ragged-red fiber disease, Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. In each case, the disease phenotype is expressed when the ratio of mutant to wild-type mitochondria exceeds a threshold peculiar to each disease, but usually in the 60 to 95 percent range.

Given that these are debilitating conditions, why has no cure been developed? Can you suggest a general approach that might be used to treat, or perhaps even cure, these disorders?

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Textbook Question

Researchers examined a family with an interesting distribution of Leigh syndrome symptoms. In this disorder, individuals may show a progressive loss of motor function (ataxia, A) with peripheral neuropathy (PN, meaning impairment of the peripheral nerves). A mitochondrial DNA (mtDNA) mutation that reduces ATPase activity was identified in various tissues of affected individuals. The accompanying table summarizes the presence of symptoms in an extended family.

Develop a pedigree that summarizes the information presented in the table.

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Textbook Question

Researchers examined a family with an interesting distribution of Leigh syndrome symptoms. In this disorder, individuals may show a progressive loss of motor function (ataxia, A) with peripheral neuropathy (PN, meaning impairment of the peripheral nerves). A mitochondrial DNA (mtDNA) mutation that reduces ATPase activity was identified in various tissues of affected individuals. The accompanying table summarizes the presence of symptoms in an extended family.

Provide an explanation for the pattern of inheritance of the disease. What term describes this pattern?

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Textbook Question

Researchers examined a family with an interesting distribution of Leigh syndrome symptoms. In this disorder, individuals may show a progressive loss of motor function (ataxia, A) with peripheral neuropathy (PN, meaning impairment of the peripheral nerves). A mitochondrial DNA (mtDNA) mutation that reduces ATPase activity was identified in various tissues of affected individuals. The accompanying table summarizes the presence of symptoms in an extended family.

How can some individuals in the same family show such variation in symptoms? What term, as related to organelle heredity, describes such variation?

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