Page 275 - Textbook of Pathology, 6th Edition

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CHAPTER 10

Figure 10.4 Common structural abnormalities of human chromosomes.

TRANSLOCATIONS. Translocation means crossing over or RING CHROMOSOME. A ring of chromosome is formed
exchange of fragment of chromosome which may occur by a break at both the telomeric (terminal) ends of a
between non-homologous or homologous chromosomes. chromosome followed by deletion of the broken fragment
There are two main types of translocations: reciprocal in and then end-to-end fusion. The consequences of ring
about two-third and Robertsonian in one-third cases: chromosome depend upon the amount of genetic material Genetic and Paediatric Diseases
Reciprocal translocation is the exchange of genetic lost due to break.
material between two non-homologous (heterologous) ISOCHROMOSOME. When centromere, rather than divi-
chromosomes without involving centromere (acentric). Such ding parallel to the long axis, instead divides transverse to
translocations occur due to single breaks in both the the long axis of chromosome, it results in either two short
chromosomes and the exchange is detected by banding arms only or two long arms only called isochromosomes.
techniques. Reciprocal translocation may be balanced The example involving isochromosome of X-chromosome is
(without any loss of genetic material during the exchange) seen in some cases (15%) of Turner’s syndrome.
or unbalanced (with some loss of genetic material).
i) Balanced reciprocal translocation is more common and the
individual is phenotypically normal e.g. translocation SINGLE-GENE DEFECTS
between long arm (q) of chromosomes 22 and long arm (q) (MENDELIAN DISORDERS)
of chromosome 9 written as 46, XX, t (9;22). This translocation
is termed Philadelphia chromosome seen in most cases of In order to unravel causes of disease at genetic level,
chronic myeloid leukaemia (page 355). spectacular advances have been made in human genetics.
ii) Unbalanced reciprocal translocations are less common and With mapping of human genome consisting of about 30,000
account for repeated abortions and malformed children. genes, it is possible to perform molecular profiling of diseases
Robertsonian translocation is less common than reci- at genetic level.
procal translocation. In this, there is fusion of two acrocentric The classic laws of inheritance of characteristics or traits
chromosomes (having very short arms) at the centromere were outlined by Austrian monk Gregor Mendel in 1866
(centric fusion) with loss of short arms. The result of this based on his observations of cross-breeding of red and white
fusion is one very large chromosome and the other very small garden peas. Single-gene defects follow the classic mendelian
one. Individuals born with Robertsonian translocation may patterns of inheritance and are also called mendelian
be phenotypically normal but suffer from infertility and are disorders. These disorders are the result of mutation of a
at higher risk of producing malformed children in the next single gene of large effect.
progeny.
MUTATIONS. The term mutation is applied to permanent
DELETIONS. Loss of genetic material from the chromosome change in the DNA of the cell. Mutations affecting germ cells
is called deletion. Deletion may be from the terminal or
middle portion of the chromosome. The examples of deletion are transmitted to the next progeny producing inherited
diseases, while the mutations affecting somatic cells give rise
are: cri du chat (named after cry of infant like that of a cat)
syndrome (deletion of short arm of chromosome 5) and to various cancers and congenital malformations. Presently,
several cancers with hereditary basis (e.g. retinoblastoma following types of mutations have been described:
with deletion of long arm of chromosome 13, Wilms’ tumour i) Point mutation is the result of substitution of a single
with deletion of short arm of chromosome 11). nucleotide base by a different base i.e. replacement of an
INVERSION. Inversion is a form of rearrangement invol- amino acid by another e.g. in sickle cell anaemia there is point
ving breaks of a single chromosome at two points. Inversion mutation by substitution of glutamic acid by valine in the
may be pericentric or paracentric, depending upon whether polypeptide chain.
the rotation occurs at the centromere or at the acentric portion ii) Stop codon or nonsense mutation refers to a type of point
of the arm of chromosome. Inversions are not associated with mutation in which the protein chain is prematurely
any abnormality. terminated or truncated.