MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 1 of 7
1) Large number of questions will be our understanding of inheritance patterns
(including pedigrees, autosomal, sex linked traits).
2) Have a good understanding of Karyotype analysis (ex: Trisomy)
3) Clinical Pathology book is a suggested read, but don’t get bogged down with too
many details. Focus on the overall picture.
4) Concentrate of Chromosome abnormalities (when, how they occur)
a) Normal: 46XX, 46XY; aneuploidy 47XX, 47XY
b) Down’s Syndrome, mosaicism
c) Turner’s
d) Lyon Hypothesis
e) X Inactivation
f) Klinefelter Syndrome
5) Lecture went pretty much through the powerpoints. I’ve added a few comments here
and there. Please review the powerpoints for corresponding images.
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GENETIC DISEASES
Lifetime frequency of genetic diseases is estimated at 670 per 1000
50% of spontaneous abortuses during early gestation have demonstrable
chromosome abnormality
About 1% all newborn infants have a gross chromosomal abnormality
GENETIC DISEASES
About 5% of individuals under the age of 25 develop a serious disease with
a significant genetic component
HUMAN GENOME PROJECT
Sequence entire human genome consisting of 3 billion base pairs of
information
Identify the genetic code for the estimated 35,000 functional genes
Identify regulatory elements controlling expression of genes
Essentially completed
IDENTIFICATION OF MUTANT GENES
FUNCTIONAL CLONING - knowledge of abnormal gene product and the
corresponding protein
POSITIONAL CLONING - no knowledge of abnormal gene product or
protein, gene isolated by linkage analysis, mapping to a particular
chromosome and its proximity to marker genes
MUTATIONS
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Mutations are permanent changes in the sequence of DNA
• Mutations that affect the germ cells are transmitted to the progeny and can
give rise to inherited diseases.
MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 2 of 7
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Somatic mutations are not hereditary, never the less can result in serious
diseases such as cancer or some congenital malformations.
CLASSIFICATION OF MUTATIONS
Genome mutations - loss or gain of whole chromosomes, giving rise to
monosomy or trisomy
Chromosome mutations - translocations or rearrangement of chromosomal
material
Gene mutations - most common cause of genetic disorders, point mutations,
single nucleotide substitutions
POINT MUTATIONS WITHIN CODING SEQUENCES
Silent or Synonymous mutation - new codon codes for the same amino acid
Missense mutation - new codon codes for a different amino acid (Sickle Cell
Anemia)
Nonsense mutation - new codon is a termination codon leading to
incomplete protein product
POINT MUTAIONS WITHIN NONCODING SEQUENCES
Effects on binding of transcription factors, resulting in either overproduction
or underproduction of protein product
Effects on processing of mRNA, improper splicing out of intervening
sequences (introns) and linking of exons
mRNA stability - mRNA is degraded prior to translation of protein product
FRAMESHIFT MUTATIONS
Deletions - single or multiple base
Insertions - single or multiple base
SINGLE BASE DELETION
Single base deletion at the ABO (glycosyltranferase) locus resulting in a
frameshift mutation rsulting in the formation of the O allele
CYSTIC FIBROSIS
Most common cause of cystic fibrosis is a 3 base pair deletion resulting in
the loss of a phenylalanine amino acid at position 508.
The gene coding for Cystic Fibrosis is the Cystic Fibrosis Transmembrane
Conductance Regulator protein (CFTR). The CFTR protein forms a
Chloride Channel which when mutated results in a severely viscid mucus in
the lungs.
TAY-SACHS DISEASE
MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 3 of 7
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Lysosomal storage disease resulting from the accumulation of GM2
gangliosides resulting from a severe deficiency of the enzyme
hexosaminidase A.
Mutation is the result of a four base insertion in the gene coding for the
TRINUCLEOTIDE REPEAT
MUTATIONS
Mutations are characterized by the amplification of a sequence of 3
nucleotides
Fragile X Syndrome (breaking of chromosome) - normal individuals
average 29 repeats of the sequence CGG within the FMR-1 gene,
individuals with Fragile X have between 250 - 4,000 tandem repeats of the
CGG sequence.
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FUNCTIONAL CONSEQUENCES OF MUTATIONS
Failure to complete a metabolic pathway (albinism)
Accumulation of unmetabolized substrate (PKU phenylketonuria)
Storage of an intermediary metabolite (Tay-Sachs Disease)
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FUNCTIONAL CONSEQUENCES OF MUTATIONS
Formation of an abnormal end product (Sickle Cell Anemia)
Defects in structural proteins (Marfan Syndrome)
Defects associated with receptor proteins (Familial Hypercholesterolemia)
TRANSMISSION PATTERNS OF SINGLE-GENE MENDELIAN DISORDERS
• Autosomal Dominant
• Autosomal Recessive
• X-linked Dominant
• X-linked Recessive
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AUTOSOMAL RECESSIVE DISORDERS
Lysosomal Storage Diseases - result from the accumulation or storage of
unmetabolized normal substrates in the lysosomes
Result in mutations in genes coding for lysosomal hydrolases
Classified on the basis of material retained within the lysosome
Autosomal recessive disorders involve missing/inactivated enzymes, and accumulation of
a product/substrate.
MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 4 of 7
- Tends to increase failure rates of metabolic pathways. Some examples:
Albinism, PKU.
- Expressed Male/Female equally. Homozygous = 25%
Consanguinity increases likelihood of autosomal recessive diseases.
AUTOSOMAL DOMINANT DISORDERS
- Normally Heterozygous at a rate of 50% in offspring (Homozygous usually lethal)
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TAY-SACHS DISEASE
Lysosomal storage disease resulting from the accumulation of GM2
gangliosides resulting from a severe deficiency of the enzyme
hexosaminidase A.
Mutation is the result of a four base insertion in the gene coding for the
The disease is predominantly seen in Ashkenazi Jews where the carrier rate
is 1 in 30
Accumulation of GM2 ganglioside in the neurons of the central and
autonomic nervous systems
Neurons are ballooned with large cytoplasmic vacuoles
The ganglion cells within the retina also swell and give a characteristic
cherry-red spot in the macula of the eye
Affected infants begin to manifest symptoms at about 6 months, showing
signs of motor and mental deterioration
Infants typically exhibit severe muscular flaccidity, develop blindness, and
die between 2 and 3 years of age
GAUCHER DISEASE
Accumulation of glucosylceramide primarily in the lysosomes of
macrophages
Disease results from the deficiency in the enzyme glucocerebrosidase
A variety of single nucleotide mutations occur in th -subunit found on
chromosome 1q21
Enlargement of the spleen with cells having a foamy cytoplasm and
eccentrically located nuclei
Classified into 3 distinct types based upon age of onset and degree of
neurologic involvement
MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 5 of 7
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Most common in Jews of European stock
AUTOSOMAL RECESSIVE DISORDERS
Glycogen Storage Diseases
Accumulation of glycogen which is a large glucose polymer of 20,000 to
30,000 glucose units per molecule
Accumulation is principally in the liver, skeletal muscle, and heart
Results from a deficiency in one of the enzymes involved in the synthesis or
sequential degradation of glycogen
Von Gierke Disease - is characterized by the accumulation of glycogen in
the liver as a result of a deficiency in glucose-6-phosphate
Disorder is seen during infancy or early childhood and manifests itself in
hepatomegaly and hypoglycemia
CYTOGENETICS AND THE IDENTIFICATION OF CHROMOSOMAL
ABNORMALITIES
• Chromosomal karyotype - the procedure of producing a chromosome spread
is to arrest mitosis in dividing cells in metaphase (most condensed form)
with colchicine and then to stain the chromosomes
• Chromosome banding - pattern of bands is unique to each chromosome,
allows pairing of homologous chromosomes and identification of
chromosome abnormalities
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CHROMOSOME BANDING
Most common staining method employs Giesma stain and is referred to as G
banding
G banding can identify between 400 to 800 bands per haploid set
CHROMOSOME
CLASSIFICATION
Metacentric - centromere is exactly in the middle (numbers 1,3,19,20)
Submetacentric - centromere divides the chromosome into a short arm (p)
and a long arm (q)
Acrocentric - very short arms or stalks and satellites attached to an
eccentrically located centromere (numbers 13,14,15,21,22, and Y)
MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 6 of 7
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RECIPROCAL TRANSLOCATIONS
Balanced with no loss of genetic material, phenotypically normal
Carriers of balanced translocations are at risk for producing offspring with
unbalanced karyotypes and severe phenotypic abnormalities
ROBERTSONIAN TRANSLOCATION
Two non-homologous acrocentric chromosomes break near their
centromeres, after which the long arms fuse to form one large metacentric
chromosome
Very little genetic information is lost and is usually associated with a normal
phenotype
Approximately 1 in 1000 apparently normal individuals have a Robertsonian
translocation
NUMERICAL CHROMOSOMAL ABNORMALITIES
Nondisjunction is the major cause of numerical chromosomal abnormalities
Results from the failure of paired chromosomes or chromatids to separate
and move to opposite poles of the spindle at anaphase either during mitosis
or meiosis
When nondisjunction occurs during gametogensis, the gametes formed have
either an extra chromosome (n + 1) or one less chromosome (n - 1)
SYNDROMES OF AUTOSOMAL CHROMOSOMES
Trisomy 21 Down Syndrome - single most common cause of mental
retardation
Results primarily from nondisjunction during the first meiotic division
(maternal)
4% of cases result from a Robertsonian translocation of an extra long arm
of chromosome 21 to an acrocentric chromosome
1% of Down syndrome patients are mosaics, having a mixture of cells with
46 and 47 chromosomes
DOWN SYNDROME
Mosaicism is caused by nondisjunction during mitosis of a somatic cell in
the early stages of embryogenesis
Maternal age has a strong influence on the incidence of trisomy 21. It occurs
1e in 1550 live births to women under the age of 20 years, and 1 in 25 in
mothers over 45 years of age
Only a small region band 22q22.1 is required to be trisomic for the
syndrome
MOD #59
Tues, 05/06/03, 11am
Dr. Eisnenberg
Robert Abbate
Page 7 of 7
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SYNDROMES OF THE SEX CHROMOSOMES
Y chromosome - The testis determining gene is located in a 230-kb region
near the end of the short arm of the Y chromosome
X chromosome - inactivation of either the maternal or paternal X
chromosome occurs at random among all the cells of the blastocyst at about
16th day of embryonic life, Lyon hypothesis, Barr body
SYNDROMES OF THE SEX CHROMOSOMES
Klinefelter Syndrome (47, XXY) - male hypogonadism that occurs when
there are two or more X chromosomes and one or more Y chromosomes
Incidence is approximately 1 in 850 male births
Principle cause of reduced spermatogenesis and male infertility
KLINEFELTER SYNDROME
Most patients have a distinctive body habitus with an increase in length
between the soles and pubic bone, which creates the appearance of an
elongated body
Small atrophic testes, often associated with a small penis
Lack of secondary male characteristics such as deep voice, beard, and male
distribution of pubic hair
TURNER SYNDROME
Turner Syndrome results from complete or partial monosomy of the X
chromosome and is characterized primarily by hypogonadism in phenotypic
females
57% of patients are missing an entire X chromosome, resulting in a (45,X )
karyotype
Most common sex chromosome abnormality in females
X-LINKED DISORDERS
Gene responsible for the disease resides on the X chromosome
X-linked traits can be dominant or recessive
Lack of transmission from father to son
Most X-linked traits are recessive so that heterozygous females do not
exhibit the disease