The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment

Huntington's Disease: The Discovery Of The Huntingtin Gene

As previously mentioned, HTT was first mapped to a specific chromosome in 1983. At that time, James F. Gusella and colleagues carried out a study to determine whether they could identify a DNA probe that would show an HD-associated restriction fragment length polymorphism (RFLP) when used in Southern blot analyses of chromosomal DNA digested with the restriction enzyme HindIII (palindromic recognition sequence 5'-AAGCTT-3'). The team identified one probe out of 12 tested, called G8, that showed a specific RFLP pattern associated with HD in two large families with a history of the disease (Gusella et al., 1983). Using the G8 probe, they next identified two HindIII sites (called H1 and H2) that were palindromic within this chromosomal region. DNA fragments at these sites vary in length among different HD lineages. Because researchers used two large pedigrees in these experiments, they were able to obtain statistical support for their discovery (Figure 3). To obtain this pedigree information, Nancy Wexler, a prominent HD researcher, followed up on reports of a high incidence of HD in two Venezuelan communities located near Lake Maracaibo. Through her visits to the Lake Maracaibo region, Wexler found that the region's HD had originated with a single founder, suggesting that all affected individuals would carry the same original mutation as the founder. Over a period of more than 20 years, Wexler's research team was able to establish extensive pedigrees with medical histories. Together with a large HD-affected family in Ohio, the Venezuelan family provided the necessary variation among the H1 and H2 HindIII restriction site patterns that segregated with the HD in both families (Figure 4). This played a key role in mapping the HD gene (Gusella et al., 1983).

Genetic Mutation

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What Are Translocations?

Translocations, in genetics, happen when chromosomes break and the pieces attach to other chromosomes. This mixing of genetic material has important results. The resultant chromosomes are lacking in some genetic information and have excessive amounts of some. Many important clinical conditions like Down syndrome and chronic myelogenous leukemia result from translocation mutations. 

A change in chromosome structure and content caused by translocation is a translocation mutation. Many genes may be transferred between chromosomes. Such translocation mutations can cause disorders of growth, development, and function of the body's cells and systems.

Human cell nuclei have 23 pairs of chromosomes. Twenty-two of them are paired (called autosomes) and numbered 1 to 22. The last pair is the sex chromosomes (X and Y). Each chromosome has two arms, named p and q. These two arms are joined at a structure called the centromere.

A translocation chromosome mutation can be of two types — reciprocal and Robertsonian. In a reciprocal translocation, two different chromosomes have exchanged pieces with each other. In a Robertsonian translocation, an entire chromosome attaches to another at the centromere.

As long as no genetic material is gained or lost in the cell, translocations are called balanced translocations. When genetic material is lost or increased, it is an unbalanced translocation.

Changes in chromosome structure affect many genes and disrupt protein synthesis of the cell. Disturbance of protein synthesis can affect the structure and function of cells and tissues. Apart from translocations, the changes in chromosome structure are:

Deletions. This happens when a chromosome breaks and part of its genetic material is lost. Deletions can be small or large and can involve from a few to hundreds of genes. An example of deletion is the 22q11.2 deletion syndrome, which causes defects of the heart, mouth, throat, brain, kidneys, and other organs of affected children. 

Duplications. This happens when there is abnormal copying of part or whole of the genetic material of a chromosome. The cell then has extra copies of genetic material from the copied segment. 

Inversions. This happens when a chromosome breaks in two places. The broken piece turns around and attaches to the chromosome. Some genetic information may be lost. Inversions may involve the centromere.

Isochromosomes. These chromosomes have two identical arms. Instead of the usual one p and one q arm, isochromosomes have two p or two q arms. They're lacking in genetic material from the missing arm and have twice the material from the extra arm. 

Dicentric chromosomes. These chromosomes have two centromeres. They result from the fusion of two chromosome pieces that each have a centromere. Dicentric chromosomes are unstable and often have lost some genetic material.

Ring chromosomes. These are formed when the ends of a chromosome break off. The arms then join to form a circular structure. Some genetic material is lost, and the centromere may or may not be present in the ring. 

The human body has millions of cells. Changes in chromosome structure in any individual cell are probably of no importance. That one cell won't function well and might die soon. Translocations are important when they occur in a large population of cells.

Translocation mutations are most harmful when they occur in a sperm, ovum, or zygote. At that time, there is only one copy of each chromosome. Any loss or addition of genetic material to a chromosome can be catastrophic. The one cell multiplies into millions of cells, forming the tissues and organs of a human. The translocation and its changes in genetic information will affect each cell. Sometimes, the translocation happens later, after conception. There will be two populations of cells, one with normal chromosomes and one with the translocation. This is known as mosaicism.

Translocation mutations can be unimportant to the person who has them. For example, a person may have a balanced translocation between chromosomes 7 and 21. The q arms of each chromosome have been switched. But this person has all the genetic material required for normal protein synthesis and function. They have no health problems at all because the chromosome translocation is balanced.

Sperm and ova are formed for reproduction, and each pair of chromosomes is split up. The sperm and ova have only one copy of each chromosome. These reproductive cells might have a chromosome 7 with the 21q attached. This sperm or ova also has a normal chromosome 21. When it combines with the opposite reproductive cell to form a zygote, there will be three 21q in the cell. The baby will be born with three copies of the q arm of chromosome 21 and will have the manifestations of trisomy 21 (Down syndrome). 

Down syndrome. This is usually caused by chromosomal non-disjunction. The sperm or ova has two full chromosomes 21, and the zygote ends up with three (trisomy 21). But a small proportion of cases are caused by chromosomal translocation, most often between chromosomes 14 and 21. The child has two full chromosomes 21, and a 21q attached to chromosome 14. The q arm of chromosome 21 appears to carry the genetic material that causes the Down syndrome manifestations. These children have serious anomalies of the heart, intestines, and spine. Later, these children have hypothyroidism, diabetes, vision and hearing issues, and variable intellectual disability.

Chronic myelogenous leukemia (CML). This blood cancer is associated with a chromosomal translocation between chromosomes 9 and 22. A part of chromosome 9 attaches to chromosome 22. The changed chromosome 22 is called the Philadelphia chromosome. This chromosome disorder causes the formation of tyrosine kinase, which helps cancer cells to grow. The Philadelphia chromosome is also sometimes found in acute lymphocytic leukemia.

Lymphoma and acute myeloid leukemia (AML). Chromosomal translocation between chromosomes 8 and 11 can cause myeloproliferative disorders, which lead to acute myeloid leukemia. It also causes lymphoma.

Some facts about chromosomal translocations:

Chromosomal translocations can be catastrophic or harmless. If you have a balanced translocation, you can be healthy throughout life. Problems only happen with reproduction.

Chromosomal translocations may be inherited from parents or arise anew around the time of conception.

There is no cure for chromosomal translocations. They're usually present in each cell of your body and will remain for life.

Translocations are not infectious. You can have social interactions and sexual contact without fear. You can also donate blood. 

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