cell division and mutations
For a better understanding of heredity and the genetics involved in Progeria, a short explanation is given of the process of cell division in humans, and the consequences of mutations. Mutations are once-only, spontaneously occurring changes in hereditary elements. Progeria is also caused by a mutation. In the case of Progeria it is not the gene that directly causes the disorder, but a poorly – or non-functioning protein, which is created using the code that is provided by that gene.
The human body is made up out of billions of cells. These cells are responsible for all the processes in the body. The human cell is enclosed by a cell membrane; inside it is a fluid, called the cytoplasm, in which a cell nucleus and cell organelles are found.
the cell nucleus and chromosomes
The cell nucleus contains the human chromosomes. All humans have 46 chromosomes. Of these 46, 22 chromosomes occur in pairs (called autosomes), which are found in men and in women. The remaining two chromosomes are called the sex chromosomes: the X-chromosome and the Y-chromosome. Men have one X-chromosome and one Y-chromosome, women have two X-chromosomes.
If a disorder can be inherited from the autosomes, this implies that the disorder is not linked to a specific sex. Progeria is an example of an autosomal, non-sex-linked, disorder: it occurs with boys as frequently as with girls.
The cell nucleus is enclosed by a membrane, a thin skin that is often referred to as the ‘nuclear envelope’. The cell membrane has pores that enable information to be transmitted between the cell nucleus and the cytoplasm. In this way information can be passed throughout the body.
DNA and genes
A cell’s appearance, and what it can, and cannot do, is determined and regulated by the genetic material in the cell, the DNA. Specific segments of the DNA contain the codes for the characteristics of a given cell. These specific segments of the DNA are called genes. Every gene encodes for a particular protein, and all proteins together result in the creation and existence of cells.
Cells, therefore, also contain the genetic information that determines the features of the body. This information is found in the DNA, or deoxyribonucleic acid. As a result, the DNA (short for deoxyribonucleic acid) is the molecule bearing hereditary information.
DNA is made up of four different bases: thymine (T), adenine (A), guanine (G), and cytosine (C). These bases combine into many different sequences, which makes the DNA of a person unique. The bases form codes that can be read, for instance TAGC, or CGTA. A chromosome is made up of long rolled up strings of this genetic material. A chromosome is essentially DNA, only it is a large quantity of it all together, and stacked in a special way.
The individual genes are located on the DNA. A gene is a segment of DNA with a specific function and is regarded as a natural unit of hereditary material. A gene carries the information for specific hereditary characteristics of a cell. For instance, genes contain the information for the colour of skin or hair. Plants have the most genes: over 50,000. Mammals, like man and mice, have approximately 30,000 genes; insects between 10,000 and 20,000. All the genes of an organism together are called the genome.
The human genome contains 3 billion base pairs of letters A,C,T and G.
The cells reproduce by cell division. This happens as follows:
During reproduction (a part of) the DNA is passed on to the offspring, packaged as chromosomes. In normal cell division (mitosis), the DNA in the original cell is copied and every daughter cell receives a full copy of the total genome. In cell division that creates sex cells (meiosis), every daughter cell receives only half of the DNA from the mother cell. This happens in both men, to form sperm cells, as in women, to form egg cells. When the sex cells fuse together they also merge their DNA. As a result the newly formed organism also has the normal amount of DNA. The characteristics of the new organism, as determined by the DNA, therefore originate from both parents.
dominant or recessive
In the cell there are two copies of each chromosome. One is originally from the father, and one originally from the mother. Each gene is present twice. Thus, there are two genes responsible for every feature. The genes can be unequal in the ‘strength’ of their functioning. With a dominant gene, that gene always is always represented in a particular feature. A recessive gene is always overruled by a dominant gene. People that have a recessive gene that causes a disease and another, healthy, gene, will not be affected by that disease, because the healthy gene is the dominant gene and does not allow the disease to surface. A recessive gene can only cause a disease if the other gene is also recessive.
The gene that causes Progeria is a dominant gene; the other, normal gene, cannot cancel the effects of the dominant gene. That is how the disease Progeria arises.
dominant gene A recessive gene b
dominant gene A AA: dominant feature Ab: dominant feature
recessive gene b bA: dominant feature bb: recessive feature
A dominant feature surfaces in 75% of the cases; a recessive feature in 25% of the cases.
An alteration in a gene is called a mutation. A mutation causes the code of the gene to change, which in turn causes a protein to be created with a different function or form.
new mutation or inherited mutation
When a couple has a child with a deviant gene due to a recent change or mutation, then this mutation may have occurred at various moments. It may have happened during the forming of the single sex cell out of which the child originated, but also earlier (in the parent), or later (in the child). With Progeria, the mutation mostly occurs after conception, in the child.
When the mutation has occurred earlier, then several cells of the parent concerned will contain that mutation. This parent will have a mixture of cells with and without the mutation: this is also called a mosaic. The number of cells that contain the mutation will vary, depending on when the mutation has occurred. Because of this, the mosaic can be present in various body tissue, or only in the sex cells. If one of the parents has the mutation in the sex cells, then there is a high chance that the child will have Progeria. With Progeria, the mutation most often occurs after conception. Then the child will have a mixture of different cells. If the majority of the cells contain the mutation then the child will show symptoms of the disease. The more cells that carry the mutation, the more the symptoms of the disease will affect the child. As a result there are different forms of Progeria.
In principle, the classic form of Progeria, HGPS, is not inherited from the parents. It is almost always caused by a spontaneous mutation shortly after conception during one of the first cell divisions.
Since 2005 it has been known that the classic form of Progeria, HGPS, can also be caused by an inherited mutation. In this extremely rare case, the father or mother of the child carries the LMNA-mutation in his or her sex cells, without experiencing any effects or complaints themselves. In such a parent the LMNA-mutation has occurred in a later stage of the cell division process, and thus not all the dividing body cells contain the mutation. It can happen that in a person only the sex cells, out of which the body makes the egg cells or sperm cells, are carriers of the mutated code. In this case, this parent has a new and big chance of having a child with classic Progeria HGPS with every pregnancy.
However, there are also different forms of Progeria. These are called ‘non-classic’ forms. Children with a non-classic form of Progeria sometimes have characteristics which are also found with hereditary disorders such as Restrictive Dermopathy (RD) or Mandibuloacral Dysplasia (MAD). Children with non-classic forms also do not resemble each other as closely as HGPS patients do, and they may also experience other complaints.
Here, a Dutch child has a non-classic form of Progeria. He has a rare autosomal recessive hereditary form. Autosomal means that boys as well as girls can inherit the disorder. Recessive means that its tendency to manifest is lower than normal.
Only when the child receives the mutated gene from both his father and his mother, will the disorder surface. The chance of having a child with Progeria in this situation is 25%.
mother: ■+■ father ●+●
child: ■+●= þ ■+●= þ ●+■=þ ■+●=ý
DNA research has shown that in this specific case, both parents are carriers of an abnormal gene, but the defect is at a different location in both parents. Both parents do not have Progeria, and that is why the mutated gene must be recessive. The two defects together, however, cause the aging effects in the boy in the photo.
Autosomal recessive forms of Progeria are more common than the classic form of Progeria, HGPS.
Progeria patients hardly ever get the chance to reproduce. They often die prematurely, and besides that the disrupted hormonal development prevents the Progeria patient from becoming fertile. If they would have the possibility to reproduce, they would have a large possibility that their children would also have Progeria.
There are also reports of identical twins that were born with Progeria. All these children have since passed away.