Robbins Flashcards
These mutations cause the disease or predispose to the disease and with some exceptions, like hemoglo-binopathies, are typically not present in normal popula-tion.
Such mutations and their associated disorders are highly penetrant, meaning that the presence of the mutation is associated with the disease in a large proportion of individuals.
Because these diseases are caused by single gene mutations , they usually follow the classic Mendelian pattern of inheritance and are also referred to as Mendelian disorders. A few important exceptions to this rule are noted later.
Disorders related to mutations in single genes with large effects.
has been extremely informative in medicine since a great deal of what is known about several physiologic pathways (e.g., cholesterol transport, chloride secretion) has been learned from analysis of single gene disorders.
Although informative, these disorders are generally rare unless they are maintained in a population by strong selective forces
Study of single genes and mutations with large effects
These arise from structural or numerical alteration in the autosomes and sex chromo-somes.
Like monogenic disease they are uncommon but associated with high penetrance.
Chromosomal disorders
These are far more common than diseases in the previous two categories.
They are caused by interactions between multiple variant forms of genes and environmental factors. Such variations in genes are common within the population and are also called polymorphisms.
Complex multigenic disorders
Each such variant gene confers a small increase in disease risk, and no single susceptibility gene is necessary or sufficient to produce the disease It is only when several such polymorphisms are present in an individual that disease occurs, hence the term_____
multigenic or polygenic.
unlike_____ genes with large effects that are highly penetrant and give rise to Mendelian disorders, each polymorphism has a small effect and is of low penetrance.
mutant
Since environmental interactions are important in the pathogenesis of these diseases, they are also called multifactorial disorders.
In this category are some of the most common diseases that afflict humans, including atherosclerosis, diabetes mel-litus, hypertension, and autoimmune diseases.
Even normal traits such as height and weight are governed by polymorphisms in several genes
Multigenic
Polymorphism
A_____ is defined as a permanent change in the DNA.
mutation
Mutations that affect___ cells are transmitted to the progeny and can give rise to inherited diseases.
germ
Mutations that arise in____ cells understandably do not cause hereditary diseases but are important in the genesis of cancers and some congenital malformations.
somatic
General principles relating to the effects of gene mutations follow.
• Point mutations within coding sequences.
• Mutations within noncoding sequences.
• Deletions and insertions.
• Trinucleotide-repeat mutations.
A ______ is a change in which a single base is substituted with a different base.
It may alter the code in a triplet of bases and lead to the replacement of one amino acid by another in the gene product.
Point mutation
these mutations alter the meaning of the sequence of the encoded protein, they are often termed
missense muta-tions
missense muta-tions
If the substituted amino acid is biochemically similar to the original, typically it causes little change in the function of the protein and the mutation is called a
“_______” missense mutation.
On the other hand, a “_______” missense mutation replaces the normal amino acid with a biochemically different one.
conservative
nonconservative
An excellent example of this type is the sickle mutation affecting the B-globin chain of hemoglobin
Here the nucleotide triplet CTC (or GAG in mRNA), which encodes glutamic acid, is changed to CAC (or GUG in mRNA), which encodes valine.
This single amino acid substitution alters the physicochemical properties of hemoglobin, giving rise to sickle cell anemia.
Point mutations within coding sequences.
Non conservative missense mutation
Besides producing an amino acid substitution, a______ may change an amino acid codon to a chain terminator, or stop codon (nonsense mutation).
Taking again the example of ß-globin, a point mutation affecting the codon for glutamine (CAG) creates a stop codon (UAG) if U is substituted for C
This change leads to premature termination of B-globin gene translation, and the short peptide that is produced is rapidly degraded.
The resulting deficiency of B-globin chains can give rise to a severe form of anemia called B°-thalassemia
point mutation
Deleterious effects may also result from mutations that do not involve the exons.
Recall that transcription of DNA is initiated and regulated by promoter and enhancer sequences
Mutations within noncoding sequences
Point mutations or deletions involving these regulatory sequences may interfere with binding of transcription factors and thus lead to a marked reduction in or total lack of transcription.
Such is the case in certain forms of hereditary anemias called thalassemias.
Mutations within noncoding sequences
In addition, point mutations within introns may lead to defective splicing of intervening sequences.
This, in turn, interferes with normal processing of the initial mRNA transcripts and results in a failure to form mature mRNA.
Therefore, translation cannot take place, and the gene product is not synthesized.
Mutations within noncoding sequences.
Small deletions or insertions involving the coding sequence can have two possible effects on the encoded protein.
If the number of base pairs involved is three or a multiple of three, the reading frame will remain intact, and an abnormal protein lacking or gaining one or more amino acids will be synthesized.
If the number of affected coding bases is not a multiple of three, this will result in an alteration of the reading frame of the DNA strand, producing what is referred to as ___—.
Typically, the result is the incorporation of a variable number of incorrect amino acids followed by truncation resulting from a premature stop codon.
Deletions and insertions
frameshift mutation
belong to a special category of genetic anomaly.
These mutations are characterized by amplification of a sequence of three nucleotides.
Although the specific nucleotide sequence that undergoes amplification differs in various disorders, almost all affected sequences share the nucleotides guanine (G) and cytosine (C).
Trinucleotide-repeat mutations
For example, in fragile X syndrome, prototypical of this category of disorders, there are 250 to 4000 tandem repeats of the sequence CGG within a gene called familial mental retardation 1 (FMR1).
In normal populations the number of repeats is small, averaging
29. Such expansions of the trinucleotide sequences prevent normal expression of the FMR1 gene, thus giving rise to mental retardation.
Another distinguishing feature of trinucleotide-repeat mutations is that they are dynamic (i.e., the degree of amplification increases during gametogenesis).
Trinucleotide-repeat mutations.
is affected if a nonsense mutation creates a stop codon (chain termination mutation) within an exon. Finally, some pathogenic point mutations may lead to expression of normal amounts of a dysfunctional protein.
Translation
three major categories of genetic disorders:
(1) disorders related to mutant genes of large effect
(2) diseases with multifactorial inheritance
(3) chromosomal dis-orders.
heterogeneous group of single-gene disorders with nonclassic patterns of inheritance.
This group includes disorders resulting from
triplet-repeat mutations
those arising from mutations in mitochondrial DNA (mtDNA)
those in which the transmission is influenced by genomic imprinting or gonadal mosaicism.
by definition, are derived from one’s parents and are transmitted in the germ line through the generations and therefore are familial.
Hereditary disor-ders
simply implies “born with.”
congenital
T or F
Some congenital diseases are not genetic; for example, congenital syphilis.
True
Not all genetic diseases are congenital; individuals with______ for example, begin to manifest their condition only after their 20s or 30s.
Huntington disease
It is estimated that every individual is a carrier of______ deleterious genes, a number originally estimated from studies of populations that appears to be borne out by genomic sequencing of normal individuals.
Most of these are recessive and therefore do not have serious phenotypic effects.
About 80% to 85% of these mutations are_____. The remainder represents new mutations acquired de novo by an affected individual.
five to eight
familial
Some_____ mutations produce partial expression in the heterozygote and full expression in the homozy-gote.
autosomal
Sickle cell anemia is caused by substitution of normal hemoglobin (____) by hemoglobin S (____).
When an individual is homozygous for the mutant gene, all the hemoglobin is of the abnormal, HbS, type, and even with normal saturation of oxygen the disorder is fully expressed (i.e., sickling deformity of all red cells and hemolytic anemia)
In the heterozygote, only a proportion of the hemoglobin is HbS (the remainder being HbA), and therefore red cell sickling occurs only under unusual circumstances, such as exposure to lowered oxygen tension.
HbA
HbS
This is referred to as the sickle cell trait to differentiate it from full-blown sickle cell anemia.
Hetero recessive
Although Mendelian traits are usually described as dominant or recessive, in some cases both of the alleles of a gene pair contribute to the phenotype - a condition called______
Histocompatibility and blood group antigens are good examples of ______ inheritance.
codominance
A single mutant gene may lead to many end effects, termed______; conversely, mutations at several genetic loci may produce the same trait (genetic heterogene-ity).
pleiotropism
Sickle cell anemia is an example of______. In this hereditary disorder not only does the point mutation in the gene give rise to HbS, which predisposes the red cells to hemolysis, but also the abnormal red cells tend to cause a logjam in small vessels, inducing, for example, splenic fibrosis, organ infarcts, and bone changes.
The numerous differing end-organ derangements are all related to the primary defect in hemoglobin synthesis. On the other hand, profound childhood deafness, an apparently homogeneous clinical entity, results from many different types of autosomal recessive mutations.
Recognition of genetic heterogeneity not only is important in genetic counseling but also is relevant in the understanding of the pathogenesis of some common disorders, such as diabetes mellitus.
pleiotropism
are manifested in the heterozygous state, so at least one parent of an index case is usually affected; both males and females are affected, and both can transmit the condition.
When an affected person marries an unaffected one, every child has one chance in two of having the disease.
Autosomal dominant disorders
With every autosomal______ disorder, some proportion of patients do not have affected parents.
Such patients owe their disorder to new mutations involving either the egg or the sperm from which they were derived.
Their siblings are neither affected nor at increased risk for disease development.
The proportion of patients who develop the disease as a result of a new mutation is related to the effect of the disease on reproductive capability.
If a disease markedly reduces reproductive fitness, most cases would be expected to result from new mutations.
Many new mutations seem to occur in germ cells of relatively older fathers.
dominant
ADD
Clinical features can be modified by variations in penetrance and expressivity.
Some individuals inherit the mutant gene but are phenotypically normal. This is referred to as______
incomplete penetrance
is expressed in mathematical terms.
Thus, 50% ____ indicates that 50% of those who carry the gene express the trait.
Penetrance
if a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals, the phenomenon is called variable______.
expressivity
For example, manifestations of neurofibro-matosis type 1 range from brownish spots on the skin to multiple skin tumors and skeletal deformities.
Expressivity
The mechanisms underlying (2) are not fully understood, but they most likely result from effects of other genes or environmental factors that modify the phenotypic expression of the mutant allele.
For example, the phenotype of a patient with sickle cell anemia (resulting from mutation at the B-globin locus) is influenced by the genotype at the a-globin locus, because the latter influences the total amount of hemoglobin made (Chapter 14).
incomplete penetrance and variable expressivity
The influence of_______ factors is exemplified by individuals heterozygous for familial hypercholesterolemia.
The expression of the disease in the form of atherosclerosis is conditioned by the dietary intake of lipids.
environmental
The biochemical mechanisms of______ disorders depend upon the nature of the mutation and the type of protein affected.
autosomal dominant
- Those involved in regulation of complex metabolic pathways that are subject to feedback inhibition.
- Key structural proteins, such as collagen and cytoskeletal elements of the red cell membrane
ADD
Those involved in regulation of complex metabolic pathways that are subject to feedback inhibition.
Membrane receptors such as the low-density lipoprotein (LDL) receptor provide one such example; in______, discussed later, a 50% loss of LDL receptors results in a secondary elevation of cholesterol that, in turn, predisposes to atherosclerosis in affected heterozygotes.
familial hypercholes-terolemia
_________ it impairs the function of a normal allele.
This effect is illustrated by some forms of osteogenesis imper fecta, characterized by marked deficiency of collagen and severe skeletal abnormalities
dominant negative
T or F
Less common than loss-of-function mutations are gain-of-function mutations, which can take two forms.
True
