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ΦΥΛΟΣΥΝΔΕΤΗ ΚΑΙ ΜΙΤΟΧΟΝΔΡΙΑΚΗ ΚΛΗΡΟΝΟΜΙΚΟΤΗΤΑ ΚΕΦΑΛΑΙΟ 5 Λάρισα, 2007 Figure 5.1 The X inactivation process. The maternal (m) and paternal (p) X chromosomes are both active in the zygote and in early embryonic cells. X inactivation then takes place, resulting in cells having either an active paternal X or an active maternal X chromosome. Females are thus X chromosome mosaics, as shown in the tissue sample at the bottom of the figure. Figure 5.2 A Barr body, which is the inactive X chromosome, is visible as a densely staining chromatin mass in the interphase nucleus of a normal female's somatic cell. DNA-based tools have now supplanted Barr body assays as a means of sex determination. Figure 5.3 A pedigree showing the inheritance of hemophilia A in the European royal families. The first known carrier in the family was Queen Victoria. Note that all of the affected individuals are male. (Modified from Raven PH, Johnson GB [1992] Biology, 3rd ed. Mosby, St Louis. With permission of McGraw-Hill, New York.) Figure 5.4 Hemophilia A. A, The enlarged right knee joint of a patient with hemophilia A, demonstrating the effects of hemarthrosis. B, Extensive bruising of the left forearm and hand. (Courtesy Dr. Richard O'Brien, Primary Children's Medical Center, Salt Lake City, Utah.) Figure 5.5 A pedigree showing the inheritance of an X-linked recessive trait. Solid symbols represent affected individuals, and dotted symbols represent heterozygous carriers. Figure 5.6 Punnett square representation of the mating of a heterozygous female who carries an X-linked recessive disease gene with a normal male. X1, chromosome with normal allele; X2, chromosome with disease allele. Figure 5.7 Punnett square representation of the mating of a normal female with a male who is affected by an X-linked recessive disease. X1, chromosome with normal allele; X2, chromosome with disease allele. Figure 5.8 Punnett square representation of the mating of a carrier female with a male affected with an X-linked recessive disease. X1, chromosome with normal allele; X2, chromosome with disease allele. Figure 5.9 Pedigree demonstrating the inheritance of an X-linked dominant trait. X1, chromosome with normal allele; X2, chromosome with disease allele. Table 5-1. Comparison of the Major Attributes of X-Linked Dominant and X-Linked Recessive Inheritance Patterns* Attribute X-linked dominant X-linked recessive Recurrence risk for heterozygous female × normal male mating 50% of sons affected; 50% of daughters affected 50% of sons affected; 50% of daughters heterozygous carriers Recurrence risk for affected male × normal female mating 0% of sons affected; 100% of daughters affected 0% of sons affected; 100% of daughters heterozygous carriers Transmission pattern Vertical; disease phenotype seen in generation after generation Skipped generations may be seen, representing transmission through carrier females Sex ratio Twice as many affected females as affected males (unless disease is lethal in males) Much greater prevalence of affected males; affected homozygous females are rare Other Male-male transmission not seen; expression is less severe in female heterozygotes than in affected males Male-male transmission not seen; manifesting heterozygotes may be seen in females *Compare with the inheritance patterns for autosomal diseases shown in Table 4-1 (Chapter 4). Figure 5.10 A patient with late-stage Duchenne muscular dystrophy, showing severe muscle loss. Figure 5.11 Transverse section of gastrocnemius muscle from (A) a normal boy and (B) a boy with Duchenne muscular dystrophy. Normal muscle fiber is replaced with fat and connective tissue. Figure 5.12 The amino terminus of the dystrophin protein binds to F-actin in the cell's cytoskeleton, and its carboxyl terminus binds to elements of the dystroglycansarcoglycan complex. The latter complex of glycoproteins spans the cell membrane and binds to proteins in the extracellular matrix, such as laminin. Figure 5.13 Boys with fragile X syndrome. Note the long faces, prominent jaws, and large ears and the similar characteristics of children from different ethnic groups: Caucasian (A), Asian (B), and Hispanic (C). Figure 5.14 An X chromosome from a male with fragile X syndrome, showing an elongated, condensed region near the tip of the long arm. Figure 5.15 A pedigree showing the inheritance of the fragile X syndrome. Females who carry a premutation (50 to 230 CGG repeats) are dotted. Affected individuals are represented by solid symbols. A normal transmitting male, who carries a premutation of 70 to 90 repeat units, is designated NTM. Note that the number of repeats increases each time the mutation is passed through another female. Also, only 5% of the NTM's sisters are affected, and only 9% of his brothers are affected, but 40% of his grandsons and 16% of his granddaughters are affected. This is the Sherman paradox. Figure 5.16 Pedigree demonstrating the inheritance of a Y-linked trait. Transmission is exclusively male-male. Figure 5.17 A, Normal individuals have one red gene and one to several green genes. B, Unequal crossover causes normal variation in the number of green genes. C, Unequal crossover can produce a green dichromat with no green genes (deuteranopia). D, Unequal crossover that occurs within the red and green genes can produce a red dichromat (protanopia) or a green anomalous trichromat (deuteranomaly). E, Crossovers within the red and green genes can also produce red anomalous trichromats (protanomaly). The degree of red and green color perception depends on where the crossover occurs within the genes. (Modified from Nathans J, Merbs SL, Sung C, et al. [1989] The genes for color vision. Sci Am 260:42-49.) Figure 5.18 The circular mitochondrial DNA genome. Locations of protein-encoding genes (for reduced nicotinamide adenine dinucleotide [NADH] dehydrogenase, cytochrome c oxidase, cytochrome c oxidoreductase, and ATP synthase) are shown, as are the locations of the two ribosomal RNA genes and 22 transfer RNA genes (designated by single letters). The replication origins of the heavy (OH) and light (OL) chains and the noncoding D loop (also known as the control region) are shown. (Modified from Wallace DC [1992] Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628632.) Figure 5.19 A pedigree showing the inheritance of a disease caused by a mitochondrial DNA mutation. Only females can transmit the disease mutation to their offspring. Complete penetrance of the disease-causing mutation is shown in this pedigree, but heteroplasmy often results in incomplete penetrance for mitochondrial diseases.