|
 |
The VHL gene, genetics, and mutations
The VHL gene is a Tumor Suppressor, a class of genes that encode proteins that work to limit cell proliferation. Inactivating mutations in Tumor Suppressors result in an increased likelihood to develop tumors. However, it is important to keep in mind that tumor suppressor gene mutations, such as those seen in the VHL gene in people with von Hippel-Lindau disease, do not cause tumors directly. Rather, multiple genetic mutations must occur in a single cell in order for a tumor to develop.
In genetic terms, people with VHL gene mutations have an increased predisposition to develop tumors in certain organs. However, we cannot predict when or where tumors will develop simply based on the knowledge that a VHL gene mutation exists. We can to some extent predict the spectrum of tumors that may arise based on the type of VHL gene mutation that a person carries.
Consultation with genetic counsellors and physicians who have a strong understanding of VHL disease is necessary to determine whether a mutation falls within a certain VHL subtype.
The VHL gene is located near the end of the “short arm” of Chromosome 3, which is indicated by the “*” in Figure 1. Most genes are interrupted by stretches of DNA, called introns, that do not contain instructions for making a protein. The parts of genes that do contain protein-making instructions are called exons. The VHL gene has 3 exons and 2 introns (see Figure 2 for an example).
When genes such as VHL are expressed, the information from the DNA is translated into a protein through a messenger RNA intermediate. The messenger RNA is made from the DNA, the introns are removed and the exons are joined together through a process called RNA splicing (Figure 2.) . It is important that the process of exon joining occur correctly, or the messenger RNA will have mistakes, resulting in an improper protein being made. In the end it is the protein that is made up of a string of amino acids that typically does the work in a cell.
The basic building blocks of genes are DNA nucleotides, or “bases,” that contain adenine, thymine, cytosine, or guanine (A, T, C, or G). The sequence of the nucleotides in a gene will determine the sequence of the protein that is made from that gene. While the DNA nucleotide sequence of a gene is composed simply of A’s, T’s, C’s, and G’s, the specific order of these nucleotides is interpreted in the cell just as we are able to interpret the order of words that make up a sentence. Mutations are mistakes (or misspellings) in the gene sequence that result in a misspelled protein. The misspelling of a protein frequently affects how that protein works in a cell. Some mutations may be quite severe, such as insertions, where DNA may be added into a gene, or deletions, where a portion of the gene might be lost. In addition, some mutations affect the splicing of the messenger RNA, such that the exons are not joined correctly, which results in mistakes in the spelling of the messenger RNA.
Other mutations may have less severe effects, such as a missense mutation, where a single amino acid in a protein may be different. Take for example a famous quote from Yogi Berra, “It ain’t the heat, it’s the humility.” A single letter change in a commonly-understood sentence results in some level of puzzlement. (Try that sentence again using “humidity”.) In the case of a protein, a missense mutation may completely garble the meaning of the protein or it may cause subtle confusion in the cell.
The VHL gene is approximately 20,000 nucleotides long, and the VHL messenger RNA is approximately 5,000 nucleotides long after it is spliced. Of these 5,000 nucleotides only 639 nucleotides of the messenger RNA actually contain the information to spell out the sequence of the VHL protein. Mutations may occur at any point within these 639 nucleotides, although most are found between nucleotides 100 and 639, as is shown in Figure 3, which is borrowed from Dr Christophe Béroud and the VHLFA web site.
When mutations are reported to patients, the numbering system is based on the VHL protein sequence. The absolute amino acid position that is changed, as well as the VHL exon that is affected, is given. As is shown in Figures 2 and 3, amino acids 1-114 are found in VHL exon 1, amino acids 115-155 are in VHL exon 2, and amino acids 156-213 are in VHL exon 3.
Some patients may have received reports of mutations that used an older numbering system that was based roughly on the beginning of the gene rather than the beginning of the protein. The difference between these two numbering systems is 213 nucleotides. For example common mutations identified at nucleotide 505 in the old numbering system are now referred to as nucleotide 292 (i.e., 505 – 213 = 292), or the previous nucleotide 712 mutations are now referred to as nucleotide 499 (712 – 213 = 499).
Since three nucleotides encode a single amino acid, one divides the nucleotide position of a mutation by 3 to get the amino acid position. For example a mutation at nucleotide 450 corresponds to amino acid 150 (450 / 3 = 150), also known as codon 150. However, we cannot have fractions of amino acids. Therefore, mutations at nucleotides 499, 500, and 501 all correspond to amino acid 167 (499 / 3 = 166.33; 500 / 3 = 166.67; 501 / 3 = 167), or codon 167. Similarly, mutations at nucleotide 292 correspond to amino acid 98 (292 / 3 = 97.33). The only mutations that are not identified based on amino acid position are mutations that are found in the two introns in the VHL gene. As described earlier these mutations affect the proper splicing of the VHL messenger RNA resulting in proteins with the wrong sequence. These mutations are identified by their nucleotide position relative to the boundary between the VHL intron and the nearest exon.
While the nucleotide sequence of the VHL gene and the amino acid sequence of its protein have been known since its identification in 1993, there is still much research to be done in order to learn how particular mutations affect the activity of the protein and how this impaired activity results in VHL disease.
Additional internet resources:
The VHLFA website (www.vhl.org) provides excellent patient-oriented information that is specific for von Hippel-Lindau disease.
Genetics Home Reference is another excellent site that is written in plain language and helps to explain complicated genetic conditions:
http://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome
Gene Reviews is a genetics information resource for health care providers and researchers. Certainly suggest this site as a starting point for any health care provider who may need a refresher on VHL disease. If the language is too technical, there are additional links for consumer resources: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vhl
Gene Tests provides an up to date list of genetic testing sites: http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/2171?db=genetests&report=Full [Last edited 16-Jan-2012 ] |
| Contact Us | Copyright 1993-2012 |