Mitochondrial Inheritance

A. Introduction. Diseases that have mitochondrial inheritance are caused by mutations in the mitochondrial DNA (mtDNA). They are inherited entirely through maternal transmission because sperm mitochondria do not pass into the ovum at fertilization. An example of a mitochondrial inherited disease is Leber hereditary optic neuropathy (LHON). Other examples arc listed in Appendix A.

B. Leber hereditary optic neuropathy (LHON)

1. The characteristic dysfunction in LHON is progressive optic nerve degeneration. This results clinically in blindness.

2. Of all cases of LHON, 50% involve the ND4 gene located on mtDNA when a missense mutation changes arginine to histidine.

3. The ND4 gene encodes for a protein called subunit 4 of the NADH dehydroge-

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9 10 11 T12 13

O female QD consanguineous union

□ male yv □ O dizygous twins unspecified sex

0 deceased ^

£ affected O proband"

adopted out adopted in

(3) Total number of children (i.e., 3 daughters)

'Proband: person who brought the condition to medical attention

Figure 24-1. Family pedigree and explanation of the various symbols. (Modified from Friedman JM, Dill FJ, Hayden MR, McGillivray BC: Genetics. Malvern, PA, Williams & Wilkins, 1992, p 151.)

Cc CO

Ce CC

Cc CO

Ce CC

CC cc Cc cc

Figure 24-2. (A) Pedigree of autosomal dominant inheritance. (Huntington disease) (B) Pedigree of autosomal rccessivc inheritance, (cystic fibrosis) (C) Pedigree of X-linked recessive inheritance. (Duchenne muscular dystrophy) Note that the three affected males are siblings of unaffected mothers. (D) Pedigree of mitochondrial inheritance. (Leber hereditary optic neuropathy) Note that affected sons and daughters are siblings of an affected mother, and affected fathers do not produce affected siblings. (A-D, modified from Dudek RW: High-Yield Cell and Molecular Biology. Philadelphia, Lippincott Williams «St Wilkins, 1999, pp 64, 65,67, 68.)

Figure 24-2. (A) Pedigree of autosomal dominant inheritance. (Huntington disease) (B) Pedigree of autosomal rccessivc inheritance, (cystic fibrosis) (C) Pedigree of X-linked recessive inheritance. (Duchenne muscular dystrophy) Note that the three affected males are siblings of unaffected mothers. (D) Pedigree of mitochondrial inheritance. (Leber hereditary optic neuropathy) Note that affected sons and daughters are siblings of an affected mother, and affected fathers do not produce affected siblings. (A-D, modified from Dudek RW: High-Yield Cell and Molecular Biology. Philadelphia, Lippincott Williams «St Wilkins, 1999, pp 64, 65,67, 68.)

nase complex, which functions in the electron transport chain and the production of ATR

4. A mutation of the ND4 gene decreases the production of ATP with the result that the demands of a very active neuronal metabolism cannot be met.

V. FAMILY PEDIGREE is a graphic method of charting the family history using various symbols (Figure 24-1). Family pedigrees of various inherited diseases are shown in Figure

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