This blog is dedicated to all the Porphyria patients worldwide.
The American Porphyria Foundation will provide updates and information here, as well as on the main site - http://porphyriafoundation.com .
Saturday, May 4, 2013
The Porphyrias Consortium 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.
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
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 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
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.
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.
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.