Gene Mutations

Gene Mutations
Many congenital formations in humans are inherited, and some show a clear
mendelian pattern of inheritance. Many birth defects are directly attributable
to a change in the structure or function of a single gene, hence the name single
gene mutation. This type of defect is estimated to account for approximately
8% of all human malformations.
18 Part One: General Embryology
With the exception of the X and Y chromosomes in the male, genes exist
as pairs, or alleles, so that there are two doses for each genetic determinant,
one from the mother and one from the father. If a mutant gene produces an
abnormality in a single dose, despite the presence of a normal allele, it is a
dominant mutation. If both alleles must be abnormal (double dose) or if the
mutation is X-linked in the male, it is a recessive mutation. Gradations in the
effects of mutant genes may be a result of modifying factors.
The application of molecular biological techniques has increased our
knowledge of genes responsible for normal development. In turn, genetic
analysis of human syndromes has shown that mutations in many of these
same genes are responsible for some congenital abnormalities and childhood
diseases. Thus, the link between key genes in development and their role in
clinical syndromes is becoming clearer.
In addition to causing congenital malformations, mutations can result in
inborn errors of metabolism. These diseases, among which phenylketonuria,
homocystinuria, and galactosemia are the best known, are frequently accompanied
by or cause various degrees of mental retardation.
Diagnostic Techniques for Identifying Genetic Abnormalities
Cytogenetic analysis is used to assess chromosome number and integrity.
The technique requires dividing cells, which usually means establishing cell
cultures that are arrested in metaphase by chemical treatment. Chromosomes
are stained with Giemsa stain to reveal light and dark banding patterns
(G-bands; Fig. 1.6) unique for each chromosome. Each band represents 5 to
10×106 base pairs of DNA, whichmay include a fewto several hundred genes.
Recently, high resolution metaphase banding techniques have been developed
that demonstrate greater numbers of bands representing even smaller
pieces of DNA, thereby facilitating diagnosis of small deletions.
New molecular techniques, such as fluorescence in situ hybridization
(FISH), use specific DNA probes to identify ploidy for a few selected chromosomes.
Fluorescent probes are hybridized to chromosomes or genetic
loci using cells on a slide, and the results are visualized with a fluorescence
microscope (Fig.1.15). Spectral karyotype analysis is a technique in which
every chromosome is hybridized to a unique fluorescent probe of a different
color. Results are then analyzed by a computer.