definition and mechanism of isochromosomes , and a brief look at two examples of it ( i (Xq) an i (17p) )

2. by S.Palizban
Isochromoses
Definition ,
Mechanisms,
Examples

3.  The process of isochromosome
may occur in pre meiotic gamete,
during meiotic cell divisions or in
post zygotic cell divisions stages
3

4.  because of the abnormal
transverse misdivision of the
centromere (centric fission),
• resulting in unbalanced chromosomal
constitution
4

5. Centromere Misdivision
 Under normal separation of sister chromatid
exchange in metaphase , the centromere
will divide longitudinally, or parallel to
the long axis of the chromosome.
 An isochromosome is created when the
centromere is divided transversely, or
perpendicular to the long axis of the
chromosome.
5

6. 6

7.  The division is usually not occurring in
the centromere itself, but in a pericentric
region.
 It is proposed that these sites of
exchange contain homologous
sequences between sister chromatids.
 Although the resulting chromosome may
appear monocentric with only one
centromere, it is isodicentric with two
centromeres very close to each other;
7

8. Misdivision of the centromere can
also produce monocentric
isochromosomes, but they are not as
common as dicentric isochromosomes
8

9.  The formation may also be because
of the more complex
U-type exchange resulting in
acentric or dicentric products.
9

10. U-Type Strand Exchange
A more common mechanism in the formation of
isochromosomes is through the breakage and
fusion of sister chromatids,
most likely occurring in early anaphase of
mitosis or meiosis.
A double stranded break in the pericentric
region of the chromosome is repaired when the
sister chromatids, each containing a centromere,
are fused together.
10

11. 11

12. • This U-type exchange of genetic material
creates an isodicentric chromosome
• Misdivision of the centromere and U-type
exchange can occur in sister chromatids, thus
creating an isochromosome with genetically
identical arms.
12

13. • However, U-type exchange can also
occur for homologus chromosomes
which creates an isochromosome with
homologous arms .
• This exchange between homologues
is most likely due to homologous
sequences containing low copy
repeats .
13

14. • Regardless of the chromosome
involved in U-type exchange, the
acentric fragment of the chromosome
is lost, thus creating a partial
monosomy of genes located in that
portion of the acentric chromosome
14

15. • The most common isochromosome is the X
sex chromosome.
• Acrocentric autosomal chromosomes
13,14,15,21 and 22 are also common
candidates for isochromosome formation.
• Chromosomes containing smaller arms are
more likely to become isochromosomes
because the loss of genetic material in those
arms can be tolerated.
15

16. o In X chromosome,
the mechanism of the formation is the
U-type exchange and reunion between
the sister chromatids of the X
and frequently associated with 45, X
cell line.
16

17.  The absence of the normal cell line
indicates that i(Xq) may be
predominantly of meiotic origin
17

18. Turner Syndrome
Turner Syndrome is a condition in females
in which there is partial or complete
loss of one X chromosome.
This causes symptoms such as growth and
sexual developement problems.
18

19. In 15% of Turner syndrome patients,
the structural abnormality is
isochromosome X, which is composed
of two copies of the q arm (i(Xq)).
19

20. • A majority of i(Xq) are created by U-
type strand exchange.
• A breakage and reunion in the
pericentric region of the p arm results
in a dicentric isochromosome.
• Some of the p arm can be found in this
formation of i(Xq), but a majority of the
genetic material on the p arm is lost so it
is considered absent.
20

21. Since the p-arm of the X
chromosome contains genes that are
necessary for normal sexual
development, Turner's syndrome
patients experience phenotypic
effects
21

22. Almost all 46, X,i(Xq) individuals
manifest streak gonads.
Complete ovarian failure and
partial ovarian failure have been
reported in 91% and 9% of cases
with i(Xq) individuals.
22

23. Alternatively, the increase in dosage
of genes on the q arm may be
involved in a 10-fold increase in risk
of i(Xq) Turner's patients developing
autoimmune thyroiditis ,
a disease in which the body creates antibodies to
target and destroy thyroid cells.
23

24. Molecular Correlation to X
24

25. The critical region in X, Xq13→q27 has
127 genes and the candidate genes for
gonadal dysgenesis.
25

26. In 45,X Turner syndrome,
the haplo-sufficiency for SHOX gene
(short stature homeo-box containing gene) in
Xp may account for the short stature.
26

27. The SHOX gene is a homeobox gene ,
meaning that it helps regulate development.
The SHOX gene is composed of 6 different
exons and is located in the
pseudoautosomal region (PAR1) of the X
chromosome and Y chromosome.
both females (who have two X chromosomes) and males
(who have one X and one Y chromosome) have two
functional copies of the SHOX gene in each cell.
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28. • The SHOX protein is called a transcription factor.
The SHOX gene is part of a large family of homeobox
genes, which act during early embryonic development
to control the formation of many body structures.
• Specifically, the SHOX gene is essential for the
development of the skeleton. It plays a particularly
important role in the growth and maturation of bones
in the arms and legs.
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29.  Isochromosome 17q
29

30. Isochromosome 17q is the most frequent
neoplasia associated isochromosome and
corresponds with poor patient survival.
Lowcopy repeats, occur in the pericentric
region of the p arm, so a crossover event
in that area can create a dicentric
isochromosome through U-type strand
exchange.
30

31. The neoplasia created from i(17q) is
caused by a decrease and increase in
gene dosage from the monosomy of the
p arm and trisomy of the q arm,
respectively.
31

32. Many candidate tumour suppressor genes
are found on the lost p arm, allowing the
tumour cell population to be maintained.
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33. It is debated whether the loss of tumour
suppressor gene p53, located on 17p, is
involved in the central pathogenesis of
some neoplasia.
The presence of one p53 gene can be
functionally active, but its relation to
other oncogenes can alter its expression
levels when present only in one copy.
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34. Since the genetic sequences involved in
i(17q) neoplasia are large, it is difficult to
determine which genes, or combination of
genes, are involved in tumour growth.
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35. References
1. Roychoudhury, Manu L. Kothari, Lopa A. Mehta, Sadhana S. (2009). Essentials of
human genetics (5th ed.). Hyderabad, India: Universities Press.
2. M. Margaret, P. Tilak and S. Rajangam (2010). 45,X/47,X,i(X)(q10),i(X)
(q10)/46,X,i(X)(q10) Isochromosome Xq in Mosaic Turner syndrome .Int J Hum
Genet, 10(1-3): 77-80
3. Wolff, D. J.; Miller, A. P.; Van Dyke, D. L.; Schwartz, S.; Willard, H. F. (1996).
"Molecular definition of breakpoints associated with human Xq isochromosomes:
implications for mechanisms of formation". Am J Hum Genet. 58 (1): 154–160.
4. Rowe, L R; Lee, J-Y; Rector, L; (16 March 2009). "U-type exchange is the most
frequent mechanism for inverted duplication with terminal deletion rearrangements".
Journal of Medical Genetics. 46 (10): 694–702.
5. James R Lupski , Pawel Stankiewicz, (2005) “Genomic Disorders: Molecular
Mechanisms for Rearrangements and Conveyed Phenotypes”
6. Barbouti, Aikaterini; Stankiewicz, Pawel; Nusbaum, Chad; et .al (2004). "The
Breakpoint Region of the Most Common Isochromosome, i(17q), in Human Neoplasia
Is Characterized by a Complex Genomic Architecture with Large, Palindromic, Low-
Copy Repeats". American Journal of Human Genetics. 74: 1–10.
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36. Thanks for yourThanks for your
attentionattention
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