Chapter 5: Genetic Disorders Flashcards
About what proportion of all newborn infants possess a gross chromosomal abnormality?
1%
Serious disease with a significant genetic component develops in approximately what proportion of individuals younger than age 25 years?
5%
Define nonsense mutation.
A point mutation that changes an amino acid codon to a chain terminator, or stop codon.
Give one example of a disease caused by a “nonconservative” missense mutation.
The sickle mutation affecting the β-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.
Give one example of a disease caused by a nonsense mutation.
Taking the example of β-globin, a point mutation affecting the codon for glutamine (CAG in mRNA) creates a stop codon (UAG) if C is replaced by U. This change leads to premature termination of β-globin gene translation, and the short peptide that is produced is rapidly degraded. The resulting deficiency of β-globin chains can give rise to a severe form of anemia called β0-thalassemia.
2 ways in which mutations within noncoding sequences may result in deleterious effects and give one example for each?
- Point mutations or deletions involving promoter or enhancer 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.
- 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. Also in some cases of beta-thalassemia.
2 ways in which small deletions or insertions involving the coding sequence may result in deleterious effects and give one example for each?
- 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. Three-base deletion in the common cystic fibrosis (CF) allele results in synthesis of a protein that lacks amino acid 508 (phenylalanine). Because the deletion is a multiple of three, this is not a frameshift mutation.
- 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 a frameshift mutation. Typically the result is the incorporation of a variable number of incorrect amino acids followed by truncation resulting from a premature stop codon. Four-base insertion in the hexosaminidase A (HEXA) gene, leading to a frameshift mutation. This mutation is the major cause of Tay-Sachs disease in Ashkenazi Jews.
In addition to alterations in DNA sequence, coding genes can also undergo structural variations. Give 3 types with one example for each.
- Amplifications: Her2 in some cases of breast cancer
- Deletions: 22q microdeletion syndrome
- Translocations: So-called Philadelphia chromosome—translocation t(9;22) between the BCR and ABL genes in chronic myeloid leukemia
…that result in aberrant gain or loss of protein function.
Trinucleotide-repeat mutations: give one example.
In fragile X syndrome (FXS), prototypical of this category of disorders, there are 250 to 4000 tandem repeats of the sequence CGG within the regulatory region of 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 intellectual disability.
Define codominance and give one example.
Both of the alleles of a gene pair contribute to the phenotype. Histocompatibility and blood group antigens are good examples of codominant inheritance
Many autosomal dominant diseases arising from deleterious (loss-of-function) mutations fall into one of a few familiar patterns (also give one example for each)..?
- Diseases 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 FH, a 50% loss of LDL receptors results in a secondary elevation of cholesterol that, in turn, predisposes to atherosclerosis in affected heterozygotes.
- Key structural proteins, such as collagen and cytoskeletal elements of the red cell membrane (e.g., spectrin). The biochemical mechanisms by which a 50% reduction in the amounts of such proteins results in an abnormal phenotype are not fully understood. In some cases, especially when the gene encodes one subunit of a multimeric protein, the product of the mutant allele can interfere with the assembly of a functionally normal multimer. For example, the collagen molecule is a trimer in which the three collagen chains are arranged in a helical configuration. Each of the three collagen chains in the helix must be normal for the assembly and stability of the collagen molecule. Even with a single mutant collagen chain, normal collagen trimers cannot be formed, and hence there is a marked deficiency of collagen. In this instance the mutant allele is called dominant negative because it impairs the function of a normal allele. This effect is illustrated by some forms of osteogenesis imperfecta, characterized by marked deficiency of collagen and severe skeletal abnormalities.
NB: Enzyme proteins are not affected in autosomal dominant disorders; instead, receptors and structural proteins are involved.
Autosomal dominant diseases arising from deleterious (gain-of-function) mutations fall into one of a few familiar patterns (also give one example for each)..?
- Some mutations result in an increase in normal function of a protein, for example, excessive enzymatic activity (no example…).
- In other cases, mutations impart a wholly new activity completely unrelated to the affected protein’s normal function, as illustrated by Huntington disease. In this disease the trinucleotide-repeat mutation affecting the Huntington gene gives rise to an abnormal protein, called huntingtin, that is toxic to neurons, and hence even heterozygotes develop a neurologic deficit.
The transmission of disorders produced by gain-of-function mutations is almost always autosomal dominant, as illustrated by Huntington disease. In this disease the trinucleotide-repeat mutation affecting the Huntington gene gives rise to an abnormal protein, called huntingtin, that is toxic to neurons, and hence even heterozygotes develop a neurologic deficit.
Features of autosomal recessive disorders?
- The trait does not usually affect the parents of the affected individual, but siblings may show the disease.
- Siblings have one chance in four of having the trait (i.e., the recurrence risk is 25% for each birth).
- If the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected individual (proband) is the product of a consanguineous marriage.
- The expression of the defect tends to be more uniform than in autosomal dominant disorders.
- Complete penetrance is common.
- Onset is frequently early in life.
- Although new mutations associated with recessive disorders do occur, they are rarely detected clinically. Since the individual with a new mutation is an asymptomatic heterozygote, several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring.
- Many of the mutated genes encode enzymes. In heterozygotes, equal amounts of normal and defective enzyme are synthesized. Usually the natural “margin of safety” ensures that cells with half the usual complement of the enzyme function normally.
List X-linked recessive disorders.
- Duchenne muscular dystrophy
- Hemophilia A and B
- Chronic granulomatous disease
- Glucose-6-phosphate dehydrogenase deficiency
- Agammaglobulinemia
- Wiskott-Aldrich syndrome: a disease with immunological deficiency and reduced ability to form blood clots (WAS gene)
- Diabetes insipidus
- Lesch-Nyhan syndrome: a rare inborn error of purine metabolism characterized by the absence or deficiency of the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT)
CHAD GWenDoLiN (X-linked = male; recessive = female)
Chronic granulomatous disease
Hemophilia A and B
Agammaglobulinemia
Duchenne
G6PD deficiency
Wiskott-Aldrich
Diabetes insipidus
Lesch-Nyhan
Two examples of X-linked dominant conditions?
- Vitamin D–resistant rickets
- Alport syndrome
- Fragile X syndrome
What protein is affected in Phenylketonuria?
Phenylalanine hydroxylase
AR
What protein is affected in Tay-Sachs disease?
Hexosaminidase A
AR
What protein is affected in Severe combined immunodeficiency?
Adenosine deaminase
AR
What protein is affected in Familial hypercholesterolemia?
LDL receptor
AD
What protein is affected in Vitamin D–resistant rickets?
Vitamin D receptor
XD
What protein is affected in Marfan syndrome?
Fibrillin
AD
What protein is affected in Duchenne/Becker muscular dystrophy?
Dystrophin
XR
2 genetic diseases affecting collagen?
- Osteogenesis imperfecta
- Ehlers-Danlos syndromes
AD (minor exceptions with EDS)
What protein is affected in Hereditary spherocytosis?
Spectrin, ankyrin, or protein 4.1
75% AD 25% AR
What protein is affected in Hemophilia A?
Factor VIII
XR
What protein is affected in Cystic fibrosis?
Cystic fibrosis transmembrane conductance regulator
AR
3 main organ systems affected in Marfan?
- Skeleton
- Eyes
- Cardiovascular system
There are two fundamental mechanisms by which loss of fibrillin leads to the clinical manifestations of Marfan syndrome?
- Loss of structural support in microfibril-rich connective tissue. These fibrils provide a scaffold on which tropoelastin is deposited to form elastic fibers. Results in weakeninig of the connective tissue predominantly affecting the aorta, ligaments, and the ciliary zonules that support the lens.
- Excessive activation of transforming growth factor (TGF)-β signaling, leading to inflammation with deleterious effects on vascular smooth muscle development, and increase in the activity of metalloproteases, causing loss of extracellular matrix.
Clinical features of Marfan?
- Unusually tall stature
- Hyperlaxity
- Dolichocephaly with bossing of the frontal eminences and prominent supraorbital ridges
- Spinal deformities
- Chest deformity: pectus excavatum (deeply depressed sternum) or a pigeon-breast deformity
- Bilateral subluxation or dislocation (usually outward and upward) of the lens, referred to as ectopia lentis
- Mitral valve prolapse
- Dilation of the ascending aorta due to cystic medionecrosis
2 consequences of dilation of the ascending aorta due to cystic medionecrosis in Marfan?
- Severe aortic incompetence
- Aortic dissection
Name 6 types of EDS.
- Classic
- Hypermobility
- Vascular
- Kyphoscoliosis
- Arthrochalasia
- Dermatospraxis
