R1162X and Q1035X

Question

Hello dear expert team,

recently, the mutations R1162X and Q1035X have been detected in my genetic material. Could you please answer the following questions about this combination:
- Is there a prognosis concerning the course of the illness?
- How is the frequency of both mutations respectively of this combination?
- Is there anything in sight for these mutations concerning research and new therapeutic options?

Many thanks and best regards,

Answer

Dear questioner,
depending on the country and region, the R1162X mutations is found in less than 1% (e.g. northern Germany) up to 10% (e.g. northern Italy) of CF patients. R1162X is a well known, typical CF mutation, whose origin is assumed to be in the region around the Mediterranean Sea. Q1035X on the other hand, is very seldom – worldwide there are only single cases known up to now. The combination of both CF mutations R1162X and Q1035X is therefore very seldom (and possibly unique).

There is data that suggests, R1162X would have a mild course of the airway disease. This is based on the work of Mr. Pignatti from Italy from the year 1992 (thus already 17 years ago), who described 9 patients, who carry on both chromosomes R1162X (therefore R1162X/R1162X as mutation genotype). Mr. Pignatti estimates for this group of 9 patients the airway disease to be “mild to moderate” (“mild to moderate” however, does also mean typical CF). For Q1035X there is one description of a course of the illness in the literature. In the year 2004 the collegues Nadja Bogdanova, Bernd Dworniczak, und Jurgen Horst from the institute of human genetics of the university of Münster, Germany, described a 29-year-old CF patient, who carries on one chromosome Q1035X (in combination with F508del). The collegues from Münster described the course of the illness as mild.

It is correct on the one hand, that it is possible to draw conclusions from the inherited mutations to the average course of the illness in one group of patients with the same CFTR mutations, however the significance for the individual course of a single patient is not given. In a recent statement of an international CF expert panel it says word for word: …”These broad genotype/phenotype associations are useful in epidemiological studies,(…)it was not developed as clinical tool for individual prognostic predictions(…)the use of genotype to make statements of prognosis is not recommended….”(for the sake of completeness here comes the source: Journal of Cystic Fibrosis 7(3):179-196; 2008). The reason for this lack of predictive value for the single individual are all influence factors on the course of the illness of CF, that play a role in addition to the CFTR mutational genotype (environmental factors, other inherited factors, very important: physician and therapeutical management of the illness) – according to the actual opinion these “non-CFTR factors” have a greater meaning for the course of the illness than the sole CFTR mutational genotype.

The CF mutation R1162X is named like this, because at the point number 1162 of the CFTR protein the component “R” (R stands for the amino acid Arginin) is replaced by a stop codon (abbreviation X). This means, that the cell gets after 1162 components a signal for interruption of protein synthesis from the mutated CFTR and only this shortened CFTR protein is produced. Similarly, Q1035X can be translated: the shortened CF protein is only 1035 components long. Such mutations are named as “stop mutations”.

Therapeutical option for patients with stop mutations (all illnesses, not only CF) is in general Ataluren, as the effect of this substance is, that the preterm stop signal is ignored at the production of the protein. At the moment there is a study with Ataluren (a further study, as there have already been several) in the planning phase (German link about this: muko.info/forschung/klinische-studien/studienliste/ptc124-021.html). [Translator’s comment: list of participating German centers is left out].

Best regards,

Frauke Stanke

03.11.2014