Different classes of mutation

Question

Hello,

I want to thank you for creating this site.
My question is that when I am researching the different cystic fibrosis mutations, I see mutation class 1, 2, 3, or 4. So I wanted to know what that meant, what is worst?

thank you

Answer

Clear answer to your question, seemingly simple, requires to make some preliminary explanations.
The gene involved in cystic fibrosis is located on the short arm of the seventh pair of chromosomes. This gene called CFTR ("Cystic Fibrosis Transmembrane Conductance Regulator") codes synthesis by the body cells of the protein of the same name.
The CFTR protein functions as a carrier channel of chloride ions across the outer and inner membranes of the cells; it allows to regulate the concentrations of water and sodium salt (NaCl) within the cells but also in the liquid overlying surface which forms a protective film, in particular at the level of respiratory and digestive epithelium.
A gene, as it is the case of the CFTR gene, may have different molecular variants called "alleles": "normal" allele, one or more variants of normal alleles, which are called "polymorphisms "when they are without known pathological consequence on the operation of the encoded protein; alleles finally called" mutations "when they induce a dysfunction of the encoded protein.
Proteins whose synthesis is encoded by a gene containing CFTR mutations do not work as they should causing a decrease in the amount of CFTR channels present at the cell surface and / or quality of their operation. Consequently, the liquid surface (and mucus in it, then become thicker, more viscous) does not spread properly, forms plaques and no longer performs its functions of lubrication and protection properly.
More than 1800 CFTR mutations have been described to date by an international consortium. These mutations are divided into six classes according to the type of malfunction they entail:
For the first two classes, CFTR is little or no functional.
• Class I: these mutations lead to production of an incomplete CFTR, this is the case in mutations like G542X, R553X, R1162X, called "stop mutations" because they induce a premature termination of synthesis;
• Class II: These mutations result in incorrect folding of CFTR in space. Recognized as abnormal by the cell they are not transported to the membrane and are destroyed; mutations such as F508del, N1303K, or R560T, I507del belong to this class;
For the next two classes, the proper functioning of the CFTR protein reaching the cell surface is affected:
• Class III: they involve a failure to control the opening of the "chloride channel" (e.g. mutations G551D, G551S or S1255P);
• Class IV: they involve a failure of channel conductance, i.e. a decrease in the rate of passage of ions (that is the case for mutations R117H, R334W or R347P);
For the last two classes, a certain amount of functional protein allows reduced exchanges of ion to the surface.
• Class V: these mutations have an abnormal splicing, i.e. a defective assembly of different pieces of the protein (this is the case among other mutations 3489 10 kb C-> T, 3120 +1 G-> A , 2789 a G-> A);
• Class VI: in this class are the mutations in which we do not know the exact mechanism of dysfunction, but allow the synthesis and transport to the membrane of a certain amount of functional protein (eg, mutations 4326delTC, 4279insA, Q1412X ).
The genotype-phenotype relation is the relation between gene mutations (genotype) and visible expression (phenotype). If the close relationship between genotype F508del/F508del and exocrine pancreatic insufficiency was found soon after the discovery of the gene, the genotype-phenotype relation is far from always that simple. The phenotype is indeed the result, in a given individual, of an infinite number of possible combinations of genetic factors on the one hand and environmental factors on the other. In addition:
• genetic factors are not confined to single genotype: genes called modifiers remain to be identified; different CFTR gene, they can indeed alter the expression of mutations to enhance or mitigate;
• environmental factors such as quality of care and treatment, are subject to constant change bring progress.
The CFTR genotype alone does not predict the clinical course of a particular patient and is not sufficient in itself to assess its prognosis. At the scale of a large patient population, the genotype is however partly correlated with the severity of cystic fibrosis phenotype.
A study involving over 15,000 patients in the U.S. Registry in the period 1993 to 2002 has brought together classes of CFTR mutations in two major categories, in terms of protein dysfunction and survival prognosis, respectively "high risk" (Classes I , II and III) and "low risk" (Class IV and V). The difference of median age at death between these two categories was ten years in this population.
This study confirmed that the presence of two mutations, class I, II or III, each resulting in a significant reduction in the transport of chlorine is usually associated with a more severe phenotype of the disease. Conversely, patients with at least one mutation class IV, V or VI, due to the presence of a certain amount of functional CFTR at the cell surface, showed less severe symptoms.
Hoping to have answered your question. Sincerely.
Dr. Gilles Rault

19.07.2012