Pseudoachondroplasia

Southern

T Cutting site for restriction enzyme

Mutation introduces new target site a a

2.1 Autosomal inheritance heterozygotes, the single functional allele provides enough active protein for the cell's needs. This situation is called haplosufficiency. Thus the amount of protein is insufficient only if the mutant allele is present in two copies, producing the recessive trait.

MESSAGE In human pedigrees, an autosomal recessive disorder is revealed by the appearance of the disorder in the male and female progeny of unaffected persons.

PEDIGREE ANALYSIS OF AUTOSOMAL DOMINANT DISORDERS What pedigree patterns are expected from autosomal dominant disorders? Here the normal allele is recessive, and the abnormal allele is dominant. It may seem paradoxical that a rare disorder can be dominant, but remember that dominance and recessiveness are simply properties of how alleles act and are not defined in terms of how common they are in the population. A good example of a rare dominant phenotype with Mendelian inheritance is pseudoachondroplasia, a type of dwarfism (Figure 2-15). In regard to this gene, people with normal stature are genotypically d/d, and the dwarf phenotype in principle could be D/d or D/D. However, it is believed that the two "doses" of the D allele in the D/D genotype produce such a severe effect that this genotype is lethal. If this is true, all dwarf individuals are heterozygotes.

In pedigree analysis, the main clues for identifying an autosomal dominant disorder with Mendelian inheritance are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters. Again, the equal representation of both sexes among the affected offspring rules out inheritance via the sex chromosomes. The phenotype appears in every generation because generally the abnormal allele carried by a person must have come from a parent in the preceding generation. (Abnormal alleles can also arise de novo by the process of mutation. This event is relatively rare but must be kept in mind as a possibility.) A typical pedigree for a dominant disorder is shown in Figure 2-16. Once again, notice that Mendelian ratios are not necessarily observed in families. As with recessive disorders, persons bearing one copy of the rare A allele (A/a) are much more common than those bearing two copies (A/A), so most affected people are heterozygotes, and virtually all mat-ings that produce progeny with dominant disorders are A/a X a/a. Therefore, when the progeny of such mat-ings are totaled, a 1:1 ratio is expected of unaffected (a/a) to affected (A/a) persons.

Huntington disease is another example of a disease inherited as a dominant phenotype determined by an al-lele of a single gene. The phenotype is one of neural degeneration, leading to convulsions and premature death.

Pseudoachondroplasia Israel

Figure 2-15 The human pseudoachondroplasia phenotype, illustrated by a family of five sisters and two brothers. The phenotype is determined by a dominant allele, which we can call D, that interferes with bone growth during development. This photograph was taken upon the arrival of the family in Israel after the end of the Second World War. [UPI/Bettmann News Photos.]

Figure 2-15 The human pseudoachondroplasia phenotype, illustrated by a family of five sisters and two brothers. The phenotype is determined by a dominant allele, which we can call D, that interferes with bone growth during development. This photograph was taken upon the arrival of the family in Israel after the end of the Second World War. [UPI/Bettmann News Photos.]

0 0

Post a comment