Genes, which are made up of a substance called DNA, provide the body with a blueprint showing it how to develop and function. Sometimes changes in the genes, called mutations, cause them to function abnormally or not work at all.
Genes are contained within structures called chromosomes, which are found in the nucleus of each cell. We have 23 pairs of chromosomes, for a total of 46. Twenty-two pairs — numbered 1 to 22 (for a total of 44) — are called autosomes. We also have one pair of sex chromosomes, which determine gender. Females have two X chromosomes, while males have one X and one Y.
Each chromosome has one copy of many different genes. Since we have pairs of chromosomes, we have two copies of every gene, one copy from our mother and one from our father. Egg and sperm cells contain 23 chromosomes — or one copy of every gene. Upon fertilization, the developing fetus will inherit two copies of every gene.
In some cases, when one gene has a mutation and is nonfunctional, the second copy of the gene can compensate. In this case, you would need to have two abnormal copies of the gene to have the disease. Individuals with only one abnormal copy usually don't show any signs of the disease. The disorders that mutations in these types of genes cause are called autosomal recessive. Cystic fibrosis, sickle cell anemia and Tay-Sachs disease are among the conditions inherited this way.
In other cases, if one copy of the gene is functioning abnormally or not at all, the other copy can't compensate. The mutated gene "dominates" over the normally functioning gene, so it is called autosomal dominant. If a condition is autosomal dominant, a person who carries one copy of the gene containing a mutation will usually manifest some signs of that condition. Alagille syndrome is autosomal dominant.
When a person is carrying a mutation in an autosomal dominant gene, each egg or sperm cell has a 50 percent chance of containing the nonfunctioning gene copy and a 50 percent chance of containing the normal copy of the gene. This means that in each pregnancy, the fetus has a 50 percent chance of inheriting the autosomal dominant disorder.
Since Alagille syndrome was first described in the late 1960s, scientists suspected it was an inherited condition, based on the fact that it often ran in families. Several years ago, researchers noticed individuals with Alagille syndrome were sometimes missing a piece (called a deletion) on chromosome 20. This discovery gave them the idea that the gene that causes Alagille syndrome is probably located on the missing portion of DNA on chromosome 20. By comparing the deletions of different Alagille syndrome patients, these researchers were able to narrow down the region where the gene might be located. They then looked at different genes they knew were located in this region.
In 1997, scientists began studying a gene called Jagged1, named after a similar gene found in fruit flies. Normally, Jagged1 is involved in the normal development of the liver, heart and other organ systems. Researchers looked at the DNA sequence of the Jagged1 gene in people with Alagille syndrome and compared it to the same sequence in unaffected individuals. They found that the people with Alagille syndrome had mutations in this gene and that their affected family members carried the same gene change. Thus, they were able to prove Jagged1 is the gene that causes Alagille.
Recently a small number of patients with Alagille syndrome have been identified who have a mutation in another gene called Notch2 (and not in Jagged1).
For more information about genetics and inheritance, please visit our Division of Human Genetics and Molecular Biology's Web site.
Looking for mutations in a gene is similar to looking for a typo in a book. The genes are the instructions used to make proteins. The DNA in a gene is made up of "base pairs," called A, T, G or C. Three base pairs together are like a word that codes for an amino acid, the basic building blocks of proteins. Each protein in the body can combine with other proteins and may have many different functions. For example, proteins can make up a cell's structure, can be involved in cell-to-cell signaling or can be enzymes necessary for normal metabolism. Each gene is also divided into sections, like chapters in a book, called exons. In between each exon is extra DNA called introns. Jagged1, the gene responsible for Alagille syndrome, is made up of approximately 4,000 base pairs within 26 exons.
In some genetic disorders, each affected person has the same gene change or mutation. In these cases, the lab knows the exact spot to look for the mutation. But in Alagille syndrome, each family usually has a mutation that is different from other families' mutations, although people from the same family do share the same mutation. This makes screening more difficult, because we don't know where in the gene to start looking for the mutation. Like a proofreader searching for a typo in a book, the lab must read each exon to see if it contains a mutation. Sometimes it's in the first "chapter," or exon, but sometimes it might be at the end of the gene. Searching through the entire gene can take a lot of time.
In most cases, scientists study the Jagged1 gene in the laboratory by extracting DNA from a blood sample. Current techniques are able to identify the Jagged1 mutation in approximately 70 percent of children with Alagille syndrome. Once a mutation has been identified in an affected child, parents and other family members can undergo carrier screening.
Prenatal diagnosis can also then be offered to a family. Cells are collected either by amniocentesis or chorionic villus sampling, and scientists test the fetal DNA in those cells. While prenatal diagnosis can determine whether a fetus has inherited a mutation, it can't determine how severe the manifestations are.
Mutation analysis is starting to become available in commercial clinical labs. The types of analyses that are available vary. Some labs are starting to provide total gene sequencing, which has a very high detection rate, but is most expensive. In the Children's Hospital research lab, the mutation detection rate is above 90 percent (Warthen et al., 2005). As with any mutation testing, some patients with Alagille Syndrome will not have a mutation detected by any technique or lab.
Reviewed by Binita M. Kamath, MD
Date: January 2009