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Chromosomes
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Dr Pupak Derakhshandeh, PhD
Ass Prof Medical Science of Tehran University
Email: [email protected]
Website: http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984 (English)
http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889 (Persian)
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Trisomy 18, 47 Ch.
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Trisomy 18, 47 Ch.
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incidence of about 1 in 3,000
There is a 3:1 preponderance of females to
males
Thirty percent of affected newborns die
within the first month
50% by two months
and 90% by one year.
severe mental retardation
microcephaly
overlapping fingers, and rocker bottom feet
Neurologically they are hypertonic
Other common malformations include
congenital heart, kidney, .... abnormalities.
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Trisomy 18, 47 Ch.
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Trisomy 13 (XX/XY, 47 Ch)
has an incidence of 1 in 5,000
Forty-four percent of affected newborns
succumb in the first month of life
and 69% by six months
Only 18% of the babies born with trisomy 13
survive the first year
microcephaly
microophthalmia (small eyes)
cleft lip or cleft palate
polydactyly (extra fingers)
congenital heart defects
urogenital defects
brain malformations
severe mental retardation.
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Turner Syndrome (45 , X)
45, X
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Turner Syndrome
(45, X)
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Turner syndrome
• Only females
• One X chromosome
• Or has two X chromosomes but one is
damaged
• Short stature
• Delayed growth of the skeleton
• Sometimes heart abnormalities
• Usually infertile due to ovarian failure
• Diagnosis is by blood test (karyotype)
• 1 out of every 2,500 female live births
worldwide
• Short neck with a webbed appearance
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Kleinefelter47/XXY
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Klinefelter syndrome (47, XXY)
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In boys and men
47 chromosomes with XXY sex
chromosomes
XXY is one of the most common
chromosomal abnormalities
1 in 500 male births
the most common genetic cause of male
infertility
Often : undiagnosed : variation in clinical
presentation
Small testes , insufficient production of
testosterone , and infertility
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Klinefelter syndrome (47, XXY)
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Breast enlargement, lack of facial and
body hair, a rounded body type , to
be overweight , and be taller than
their fathers and brothers
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Learning and/or behavioral problems
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Testosterone replacement corrects
the symptoms of androgen deficiency
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Kleinefelter
XXY
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Fragile X Syndrome
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1 in 3,600 males and 1 in 4,000 to
6,000 females with the full mutation
worldwide
It is estimated that 1 in 250 females
and 1 in 700 males are carriers of
the premutation.
It is second only to Down Syndrome
as a cause of mental retardation
Fragile X syndrome appears in
children of all ethnic, racial and
socio-economic backgrounds
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Fragile X Syndrome
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most common inherited form of familial
mental retardation
(CGG)n trinucleotide expansion in the FMR1
gene leading to the typical Martin-Bell
phenotype
Clinical features vary depending on age and
seX
Expansion of a (CCG)n repeat in the FMR2
gene corresponds to the FRAXE fragile site
which lies distal to FRAXA and is also
associated with mental retardation, but it
is less frequent and lacks a consistent
phenotype
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Fragile X Syndrome
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Fragile X
Syndrome
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Chromosome abnormalities
 Abnormality
of chromosome
number or structure:
 Numerical
Abnormalities
 Structural
Abnormalities
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Structural Abnormalities
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Deletions: A portion of the
chromosome is missing or deleted
(>5 Mb).
 Paraderwilli
Syndrome (Ch 15)
 Angleman Syndrome (Ch 15)
 Imprinting
effect
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DELETIONS
 Deletion
refers to the loss of a
segment of a chromosome
 This can be terminal (close to
the end of the chromosome on
the long arm or the short arm)
 or it can be interstitial (within)
 eg.DGS
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DELETIONS
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Structural Abnormalities
• Duplications: A portion of the
chromosome is duplicated,
resulting in extra genetic
material.
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Oncogenes (c-onc, c-fos, c-myc)
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DUPLICATIONS
refers to an extra chromosomal
segment within the same
homologous chromosome or an
extra chromosomal segment on
another nonhomologous
chromosome.
 Again, the clinical findings are
highly variable depending upon the
chromosomal segments involved.
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 Gene
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expantion:
Huntington Disease/ Fragile X, ….
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Structural Abnormalities
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Translocations: When a portion of
one chromosome is transferred to
another chromosome.
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There are two main types of
translocations.
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In a reciprocal translocation,
segments from two different
chromosomes have been exchanged.
In a Robertsonian translocation, an
entire chromosome has attached to
another at the centromere.
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Reciprocal TRANSLOCATIONS
Translocation involves two
nonhomologous chromosomes (e.g.,
chromosome 2 and chromosome 6)
 Following a break in each of the
chromosomes, and subsequent
reunion
 a segment of chromosome 2
becomes attached to chromosome
6
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TRANSLOCATIONS
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Balanced reciprocal translocation
Balanced reciprocal translocation
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Structural Abnormalities
 Inversions:
A portion of the
chromosome has broken off,
turned upside down and
reattached, therefore the
genetic material is inverted.
 eg
Ch9 inv in Iran
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Inversions
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involve only one chromosome
the intervening segment is rejoined in an
inverted or opposite manner.
Since there is no loss nor gain of chromosomal
material, inversion carriers are normal
Paracentric: does not include the centromere
pericentric:inverted segment contains the
centromere
In meiosis, the normal chromosome and the
inverted chromosome will form a loop to allow
pairing of specific DNA sequences
that occur within the inversion loop result in
gametes with both deletions and duplications
inversion carriers have a relatively low risk of
having abnormal offspring.
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Inversions
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Meiosis in an individual heterozygous for a pericentric inversio
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Rings: A portion of a chromosome has
broken off and formed a circle or
ring. This can happen with or without
loss of genetic material.
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Ring
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Oncology
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Chronic Myelogenous Leukemia (CML)
a clonal expansion of transformed
hematopoietic progenitor cells:
 Myeloid
 Monocytic
 Erythroid
 Megakaryocytic
 lymphoid lineages
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Molecular level
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CML: characterized by the bcr-abl
fusion gene
reciprocal translocation
t(9;22)(q34;q11)
creating the Philadelphia (Ph)
chromosome
survival time of patients : to 5 to 7
years
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Hematology
Bone marrow
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Chronic myelogenous leukemia
(CML)
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15% to 20% of leukemias in adults
incidence of 1 to 2 cases per 100,000
population
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Chronic myelogenous leukemia
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occurs more frequently in males than in
females (ratio of 1.3 to 1)
Incidence: increases with age
the median age at presentation is
between 45 and 55 years
which is an important consideration for
the selection of therapeutic strategies
 stem-cell transplantation
 treatment with interferon-alfa (Intron
A, Roferon-A)
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The Philadelphia Chromosome
a reciprocal translocation between the
long arms of chromosome 9 and
chromosome 22
 the large segment of the c-abl gene
from chromosome 9q34
 to the part of the bcr gene on
chromosome 22q11 in a head-to-tail
fashion
 creating a hybrid bcr-abl gene that is
transcribed into a chimeric bcr-abl
mRNA
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Detection of bcr-abl
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Cytogenetic analysis
Ph chromosome in 90% of patients with
CML
Such analysis is tedious and timeconsuming
allows the examination of only 20 to 25
metaphases per bone marrow sample
misses the 5% of patients who are Phnegative but bcr-abl-positive
Despite these shortcomings, cytogenetic
analysis is the gold standard in the
diagnosis of CML.
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FISH
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Fluorescence in situ hybridization
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allows for the analysis of metaphase
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Results of FISH studies are easily
quantifiable
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fluorescence in situ hybridization (FISH)
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fluorescence in situ hybridization
(FISH)
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FISH
Bcr
Abl
AblBcr
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Abl-Bcr
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