Mutations

Question

Hello, my child has 3396delC mutation and M1101K mutation. Can you tell me something about these mutations? Thank you in advance.

Answer

Hello,
The CF genotype of your child combines two rare mutations :
- The 3396delC mutation is a mutation which causes a frameshift in reading of the CFTR gene and leads to a premature termination of the synthesis of the CFTR protein. This truncated protein is recognized as abnormal, is destroyed by the cell before reaching the membrane and therefore cannot perform its function of a chloride channel. This type of mutation, also called " stop mutation ", belongs to class 1 mutations. This mutation 3396delC , though too rare to allow to establish statistical correlations with the type of clinical course, is most likely a "CF causing mutation", say a mutation responsible for the disease when it is associated with another CF causing mutation.
- The M1101K mutation is rare although it is the second most common mutation in Hutterites (see web link for more information on this population). It was found 4 times in France including 3 times associated with symptoms (phenotype) of CF (the fourth case is that of a newborn for which it is too soon to assess the long-term effects). The nature of the mutation, say a substitution of methionine (M) by a lysine (K), its location in the position 17b of the CFTR gene, bioinformatic predictions and the few cases reported in the French and the Hutterite populations (see reference published in 1993) suggest that it is also a CF causing mutation.
Moreover, it should be noted that genotype-phenotype correlations should be interpreted with caution when it comes to making a prognosis for a given patient. Certainly, statistical analyses involving thousands of patients have led to correlations between certain combinations of mutations (genotypes) and clinical outcome (phenotype), but the sole CFTR genotype does not predict clinical outcome and therefore prognosis of the individual patient. 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 summary, the status of each patient is unique and prognostic extrapolation from genotype only is abusive. I can only recommend that you continue your child's monitoring by the multidisciplinary team of a specialized CF center able to discuss with you the treatment decisions that requires your child's condition.
Hoping to meet your expectations, I wish you a happy new year.
Sincerely.
Gilles Rault, MD, CF Centre of Roscoff
with the kind support of:
Marie- Pierre AUDREZET, PhD
Molecular Genetics , University Hospital of Brest

20.01.2014

References:
Identification of the M I I 01 K Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene and Complete Detection of Cystic Fibrosis Mutations in the Hutterite Population. Julian Zielenski et al. Am J Hum Genet : 52:609- 615, 1993.