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Genetics 101 of Porphyria

Genetics 101:  Basic genetics and inheritance

In order to better understand the Porphyrias and how the disorders are inherited, it is helpful to understand some concepts of basic genetics and inheritance patterns.

DNA, Chromosomes, and Genes:

Deoxyribonucleic acid (DNA) is a nucleic acid that contains the instructions used in the development and functioning of all known living organisms and some viruses. DNA is often compared to a set of blueprints or a recipe or a code because it contains the instructions needed to make certain proteins, which are the complex molecules that do most of the work in our bodies. Each of these proteins has a specific function in the cell, and, ultimately in how the organism develops, its physical makeup, and how it functions day-to-day. The DNA segments that carry this genetic information are called genes. The size of each gene varies greatly, and there are about 20,000 genes that are distributed along the 23 pairs of chromosomes.
A DNA molecule is a twisted double-strand of building blocks, called nucleotides.  It is like a twisted ladder, with the vertical stringers made of phosphates and sugars and the rungs made of pairs of nucleotides. There are four nucleotides in DNA:  adenine (A), thymine (T), guanine (G), and cytosine (C). Also important is that on each rung of this ladder, A always pairs with T, and G always pairs with C. These nucleotides along the ladder are like letters in a word, and put together in their specific order make up the words in a detailed set of instructions. These instructions are read using a special code, called the genetic code.
GenGenome Management Information System,
Oak Ridge National Laboratory
DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone.
Within cells, DNA is organized into long structures called chromosomes. A chromosome is like a cookbook with many recipes (or genes) that tell the body how to function. The human body is made up of trillions of cells and over 200 different cell types like various blood, liver, and brain cell types.  Each cell contains 46 chromosomes. Each chromosome can be identified by its relative size and location of the centromere, a constriction in the chromosome. 
The chromosomes come in pairs.  Since there are 46 chromosomes, there are 23 pairs of chromosomes.  One chromosome in each pair comes from the person’s father.  The other chromosome in each pair comes from the mother.
The first 22 pairs of chromosomes are called “autosomes”.  The autosomes are numbered 1-22.  These chromosomes determine an indivdual’s physical appearance and tell the body how to function day-to-day. 
The 23rd pair of chromosomes is called the “sex chromosomes”.  Parts of these chromosomes determine whether an individual will be male or female, but they also carry additional important information.  A female has two X chromosomes.  A male has one X chromosome and one Y chromosome.
Along each chromosome, there are thousands of genes. Since the chromosomes come in pairs, the genes along them also come in pairs. This means that the genes that are found on one chromosome in each pair are the same as the genes that are found on the other chromosome in that pair. The sex chromosomes are an exception.  Most of the genes that are located on the X chromosome are different from the genes that are located on the Y chromosome. For example, the ALAS2 gene, involved in X-linked Erythropoietic Protoporphyria (EPP), is on the X chromosome, but is NOT on the Y chromosome.
Each gene is a set of instructions that tells the cell how to make a specific product called a protein. These proteins have the job of telling the body how to grow and develop as well as how to do all the things that are necessary for the body to work properly every day.  Any change in one of these genes may interfere with the body’s ability to make one of these necessary proteins. A gene change is called a mutation.
Autosomal Dominant Inheritance:
Since autosomal genes always occur in pairs, with one coming from each parent, individuals with an autosomal dominant form of porphyria [Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), familial Porphyria Cutanea Tarda (f-PCT)] have one non-working gene with a mutation on one chromosome, paired with a working (or normal) gene on the other chromosome.  Usually, the non-working gene was inherited from one of the individual’s parents. Rarely, a new mutation (also called a “de novo” mutation) can occur in the affected individual and not be present in one of his parents. However, the de novo mutation will be inherited by 50% of the patient’s offspring. In individuals with an autosomal dominant form of porphyria, there is a 50% chance with each pregnancy that the non-working gene will be passed on to a child.  Some of those who inherit the non-working gene will develop symptoms.

Autosomal Recessive Inheritance:

Individuals with an autosomal recessive type of porphyria [Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EEP) and Hepatoerythropoietic Porphyria (HEP)] have a pair of genes with mutations that affects the function of the enzyme encoded by the gene. In such individuals, one mutant gene was passed on from each of their parents. If their children only inherit one mutant gene for that porphyria, which will be paired with a normal gene from the other parent, and the child will be a “carrier”, but will not have symptoms.
If two carriers of the same or similar mutant recessive gene have children, there is a 25% chance with each pregnancy that the child will inherit two mutant genes (one from each carrier parent), and these children will develop symptoms of the disease.
X-Linked Inheritance:
The “sex chromosomes” are the X-chromosome and the Y-chromosome. Females have two X-chromosomes, and males have one X-chromosome and one Y-chromosome. In X-linked disorders [for example, X-Linked Protoporphyria (XLP], the gene is located on the X-chromosome, and the risk for children depends on the gender of the affected parent. If a female has the mutation, there is a 50% risk for passing the mutation onto her children with each pregnancy.
© 1995 Greenwood Genetics Center
For a male who has the gene mutation, all of his daughters will get the mutation, but none of his sons.
© 1995 Greenwood Genetics Center
X-linked inheritance (when the mother has the mutation)
If a daughter gets the gene mutation from either her mother or her father, the daughter may or may not have symptoms, and the severity of symptoms may vary even among the females in the same family. For this reason, in most X-linked disorders, including X-Linked Protoporphyria, females who have the gene mutation are referred to as “heterozygous” for the mutation, rather than “carriers” which infers that they will not have any symptoms (as in autosomal recessive disorders). If a son gets the mother’s mutation, he will have symptoms.


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