L.3 Mutations & teratogens

Question 1

congenital malformations

Answer 1

• Disorders that are present at birth are called congenital, whether the cause is genetic, environmental, or both.
• Some congenital disorders are associated with structural defects attributable to errors in fetal development

Question 2

Karyotype

Answer 2

• Karyotypes are usually described using a shorthand system of notations in the following order: total number of chromosomes is given first, followed by the sex chromosome complement, and finally the description of abnormalities in ascending numerical order.
• a male with trisomy 21 ⇒ 47,XY, +21

Question 3

multifactorial

Answer 3

Polygenic traits are often affected by environmental factors

Question 4

point mutation

Answer 4

• involves a single base pair substitution
• cause the affected codon to signify an abnormal amino acid. The inclusion of the abnormal amino acid in the sequence of the protein may or may not be of clinical significance.
• Sickle cell anemia and 1-antiprotease deiciency are examples of point mutation disorders in which a single amino acid substitution causes signiicant dysfunction.

Question 5

frameshift mutation

Answer 5

• often changes the genetic code dramatically
• due to the addition or deletion of one or more bases, which changes the “reading frame” of the DNA sequence.
• DNA sequence is normally “read” in groups of three bases, with no spaces between codons. All of the codon triplets will be changed in the DNA downstream from a frameshift mutation, resulting in a protein with a greatly altered amino acid sequence.

*

Question 6

Normal male karyotype

Answer 6

46,XY

Question 7

Female with Down’s Syndrome

Answer 7

47,XX,+21

Question 8

Klinefelter Syndrome

Answer 8

• Individuals with Klinefelter syndrome usually have an extra X chromosome (an XXY genotype)
• symptoms : a lack of testosterone and include testicular atrophy and infertility, tall stature with long arms and legs, feminine hair distribution, gynecomastia (breast enlargement), high-pitched voice, and marginally impaired intelligence
• Testosterone therapy can achieve a dramatic reduction in the feminine characteristics associated with Klinefelter syndrome.

Question 9

euploid

Answer 9

• The union of sperm and egg results in a fertilized egg (zygote) with the full complement of 46 chromosomes:
• 22 pairs of autosomes ( do not determine sex) and 2 sex chromosomes ( females get X and X from parents, males get X and Y
• 23 pairs total; 46 chromosomes = euploid

Question 10

Aneuploidy

Answer 10

• refers to an abnormal number of chromosomes—in humans, either more or less than 46.
• Aneuploidy is most commonly caused by nondisjunction

Question 11

Nondisjuction

Answer 11

paired homologous chromosomes fail to separate normally during either the irst or the second meiotic division

Question 12

Monosomy

Answer 12

• When the abnormal germ cell (either has 22 or 24 chromosomes) combines with a normal germ cell containing 23 chromosomes, the resulting zygote will either be deicient by one chromosome (45) or have an extra chromosome (47).
• In anaphase lag, one chromosome lags behind and is therefore left out of the newly formed cell nucleus⇒ one daughter cell with normal number of chromosomes + one with a deiciency of one chromosome (MONOSOMY)

Question 13

Polysomy

Answer 13

the condition of having too many chromosomes

Question 14

crossing over.

Answer 14

• During meiosis, the homologous chromosomes normally pair up and exchange genetic alleles
• Normal crossing over involves precise gene exchange between homologues only, with no net gain or loss of DNA

Question 15

long arm

Answer 15

(q arm)

Question 16

P Arm

Answer 16

Short arm of a chromatid

Question 17

Translocations (reciprocal or Robertsonian)

Answer 17

• Reciprocal translocation, no genetic material is lost and the individual may have no symptoms or disorder. However, an individual with a reciprocal translocation is at increased risk of producing abnormal gametes.
• Robertsonian translocation: The exchange of a long chromatid arm for a short one results in the formation of one very large chromosome and one very small chromosome. responsible for a rare hereditary form of Down syndrome

Question 18

Isochromosomes

Answer 18

when the sister chromatids separate incorrectly at the centromere such that the two identical short arms remain together, as do the two long arms.

Question 19

Inversion

Answer 19

• the removal and upside-down reinsertion of a section of chromosome
• The chromosome with an inverted section may not pair up properly, resulting in duplications or loss of genes at the time of crossing over.
• Offspring of an individual with an inversion may be affected.

Question 20

deletion

Answer 20

• Loss of chromosomal material
• result from a break in the arm of a single chromosome, resulting in a fragment of DNA with no centromere.
• Chromosomal deletions have been associated with some forms of cancer, including retinoblastoma
• Deletions at both ends of a chromatid may cause the free ends to attach to one another, forming a ring chromosome.
• Deletions are more often “interstitial”, not “terminal” – i.e., an inner part of the chromosome is lost, rather than at the ends of the chromosomes

Question 21

duplication

Answer 21

• extra copies of a portion of DNA.
• The consequences of duplications are generally less severe than those from loss of genetic material.

Question 22

Mosaics

Answer 22

• Occasionally, mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement, in the same individuals, a condition referred to as mosaicism
• Mosaicism affecting the sex chromosomes is relatively common. In the division of the fertilized ovum, an error may lead to one of the daughter cells receiving three sex chromosomes, whereas the other receives only one, yielding, for example, a 45,X/47, XXX mosaic. All descendent cells derived from each of these precursors have either a 47,XXX complement or a 45, X complement. Such a patient is a mosaic variant of Turner syndrome, with the extent of the phenotypic expression dependent on the number and distribution of the 45,X cells” … “Autosomal mosaicism seems to be much less common than that involving the sex chromosomes. An error in an early mitotic division affecting the autosomes usually leads to a nonviable mosaic due to the autosomal monosomy.”. One example of a viable autosomal mosaic is Down’s Syndrome Mosaics.
  
  1. (written as: 46, XY/47,XY,+21)

Question 23

Phenotype

Answer 23

physical and biochemical attributes of an individual that are outwardly apparent.

Question 24

genotype

Answer 24

expression of the individual’s unique genetic makeup,

Question 25

Chromosomal Abnormalities

Answer 25

1. Aberrant # (aneuploidy, nondisjunction, monosomy, polysomy)
2. Abnormal chromosomal structure (translocations, inversions, deletions, duplications)
3. Autosomal Chromosome Disorders
   
   • Example: Trisomy 21 (Down’s Syndrome); Cri du Chat Syndrome (Deletion of part of the short arm of chromosome 5) ; trisomy 18 and 13 ( very rare but severe)
4. Sex Chromosome Disorders
   
   • Ex. Klinefelter Syndrome; Turner Syndrome ( only one normal X chromosome and no Y chromosome - Monosomy ) ; Multiple X Females and Double Y Males ( an extra copy of the X chromosome in females (XXX) or of the Y chromosome in males (XYY))

Question 26

Mendelian single-gene disorders

Answer 26

• result from mutations in single genes
• The affected genes may code for abnormal enzymes, structural proteins, regulatory proteins, or regulatory RNA molecules.
• A recessive gene is expressed only when the individual is homozygous for the gene; that is, the individual has two identical copies.
• Dominant genes require only one allele in order to be expressed. Mendelian disorders are generally classiied according to the location of the defective gene (autosomal or sex chromosome) and the mode of transmission (dominant or recessive).

1. Autosomal Dominant Disorders
2. Autosomal Recessive Disorders

Question 27

Autosomal Dominant Disorders

Answer 27

• mutation of a dominant gene located on one of the autosomes.
• Males and females are equally affected.
• Affected individuals usually have an affected parent.
• Unaffected individuals do not transmit the disease.
• Offspring of an affected individual (with normal mate) have a 1 in 2 chance of inheriting the disease.
• The rare mating of two individuals, each carrying one copy of the defective gene (heterozygous), results in a 3 in 4 chance of producing an affected offspring.
• Ex: Marfan Syndrome; Huntington Disease

Question 28

Huntington Disease

Answer 28

• this disease can show “genetic anticipation”, where for each generation, the onset of the disease is earlier and the clinical course can be more serious. This is due to an expansions of the repeats across subsequent generations. ⇒ type of accumulation disease
• affects neurologic function. The symptoms of mental deterioration and involuntary movements of the arms and legs do not appear until approximately age 40 years.
• Triplet repeats of more than 40 are reliably associated with development of the disease, and the greater the number of triplet repeats, the earlier the onset of symptoms
• The Huntington disease protein (huntingtin) has a long segment of glutamine amino acids that are coded by the CAG triplet repeat. The protein forms aggregates in brain tissue, which are thought to contribute to the pathogenesis of neurodegeneration.

Question 29

Autosomal Recessive Disorder

Answer 29

a mutation of a recessive genelocated on one of the autosomes.

Examples: phenylketonuria & cystic fibrosis; Albinism

• Males and females are equally affected.
• In most cases, the disease is not apparent in the parents or relatives of the affected individual, but both parents are carriers of the mutant recessive gene.
• Unaffected individuals may transmit the disease to offspring.
• The mating of two carriers (heterozygous) results in a 1 in 4 chance of producing an affected offspring and a 2 in 4 chance of producing an offspring who carries the disease.

Question 30

Why is “consanguinity” more likely to result in offspring who express autosomal recessive diseases?

Answer 30

Because recessive diseases are only expressed when both alleles for a particular gene are mutant (homozygous), they are often associated with consanguinity - mating of related individuals

Question 31

Sex-linked (X-linked) disorders

Answer 31

• Sex-linked disorders occur because of a mutation of the sex chromosomes.
• Affected individuals are almost always male.
• Affected fathers transmit the defective gene to none of their sons but to all of their daughters.
• Unaffected males do not carry the defective gene.
• A carrier female has a 1 in 2 chance of producing an affected son and a 1 in 2 chance of producing a carrier daughter.
• Females are affected only in the rare homozygous state that may occur from the mating of an affected or carrier mother and an affected father.
• Example : Hemophilia A ( bleeding disorder)

Question 32

Hemophilia A

Answer 32

bleeding disorder associated with a deiciency of factor VIII, a protein necessary for blood clotting.

Question 33

NONMENDELIAN SINGLE-GENE DISORDERS

Answer 33

1. Triple repeat
   
   • Fragile X - long repeating triplets of the sequence CGG
2. Mitochondrial gene mutations -
   
   • transmitted to daughter cells within the mitochondria when a cell divides. Mitochondrial DNA codes for enzymes involved in oxidative phosphorylation reactions, and mutations tend to cause dysfunction in tissues with high utilization of ATP such as nerve, muscle, kidney, and liver cells.
3. Genomic Imprinting
   
   • Maternal and paternal chromosomes are marked differentially within the cell (by methylation of DNA for example)
   • Example : Angelman and Prader-Willi syndromes

Question 34

polygenic and multifactorial disorders

Answer 34

• Most human traits develop in response to more than one gene; such traits are called polygenic.
• very common and result from the interaction of multiple genes and environmental inluences.
• Disorders such as high blood pressure, cancer, and diabetes are multifactorial.

Question 35

Teratogen

Answer 35

Factors that cause congenital malformation

Question 36

Environmental Causes of Teratogen

Answer 36

• Maternal/placental infections (e.g., rubella, toxoplasmosis, syphilis, cytomegalovirus, HIV)
• Maternal disease states (e.g., diabetes, phenylketonuria, endocrinopathies)
• Drugs and chemicals

Question 37

relative frequency of the causes of congenital malformations rank (%)

Answer 37

“Unknown” is the highest, followed by “Multifactorial, then Chromosomal Aberration

Question 38

Embryonic period

Answer 38

• 1^st 9 weeks – during the first 2 months; insult usually results in death (demise) of the fetus
• followed by (2) the fetal period, which continues until birth.

Question 39

Fetal period

Answer 39

• Between the third and ninth weeks of gestation the embryo is very vulnerable to teratogenesis, with the fourth and ifth weeks being the time of peak susceptibility
• organogenesis
• Fetal insults occurring after the third month are more likely to result in growth retardation or injury to normally formed organs

Question 40

list of proven teratogens

Answer 40

1. thalidomide,
2. alcohol,
3. anticonvulsants,
4. warfarin,
5. folate antagonists,
6. androgenic hormones,
7. angiotensin-converting enzyme (ACE) inhibitors,
8. organic mercury.

Question 41

Infectious agents (TORCH)

Answer 41

1. toxoplasmosis ( protozoal infection that can be contracted from ingestion of raw or undercooked meat and from contact with cat feces)
2. other ( hepatitis B, coxsackievirus B, mumps, poliovirus, and others.)
3. rubella
4. cytomegalovirus
5. herpes

Cytomegalovirus and herpes simplex virus are generally transmitted to the fetus by chronic carrier mothers. ( genital area)

Question 42

Rubella

Answer 42

• Viral
• risk begins just before conception and extends to 20 weeks’ gestation, after which the virus rarely crosses the placenta.
• Rubella-induced defects vary but typically include cataracts, deafness, and heart defects.