3121-1G-

Question

Dear Expert,

I have a 6 years old boy with 3121-1G->A and N1303K. He is PI (born with meconium ileus), and with regards to the lung disease he is not symptomatic. Can this genetics predict the severity of his lung disease?

Can you know the molecular outcome of the 3121-1G->A mutation? Is this splicing mutation results with a nonfunctional protein? Can normal splicing happen in some frequency? Is there a drug in the pipeline for amending splicing defects?

And another question with regards to 3121-1G->A, do you know when was the first time that this mutation was linked to Iraqi Jews?

Thank you very much!

Answer

Thank you for your question. The 3121-1G->A mutation was only recently linked to Iraqi Jews in 2009.[1] At present there is not a great deal of information in terms of the impact that this particular mutation has on the severity of disease in CF subjects.

The relationship between genotype, that is, the mutations in the CFTR gene, and the clinical phenotype of CF patients has been difficult to establish, in particular for lung disease. There is a high variability in phenotype within identical CFTR genotypes. [2] As modifier genes remain to be identified, consensus statements advise that clinicians should not use genotype alone to predict clinical outcomes at the time of diagnosis.[3] Furthermore, CF mutations themselves are not independent of each other in terms of predicting phenotype.[4] Despite these shortcomings, it does appear that the 3121-1G->A confers a moderate to severe phenotype,[5] and the fact that your son is pancreatic insufficient is consistent with this.
Splicing mutations generally produce small amounts of CFTR transcript and so only low levels of functional protein are formed. These are often class 1 and class 2 mutations. There has been significant progress in developing new therapies for correcting CFTR function for CF subjects with class 3 mutations, but the future is promising for additional therapies to become available for other classes of mutations as well.

Reference List

1. Reish, O., et al., Dynamic modification strategy of the Israeli carrier screening protocol: inclusion of the Oriental Jewish Group to the cystic fibrosis panel. Genet Med, 2009. 11(2): p. 101-3.
2. McKone, E.F., et al., Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet, 2003. 361(9370): p. 1671-6.
3. Castellani, C., et al., Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros, 2008. 7(3): p. 179-96.
4. Comer, D.M., et al., Clinical phenotype of cystic fibrosis patients with the G551D mutation. QJM, 2009. 102(11): p. 793-8.
5. www.genet.sickkids.on.ca/MutationDetailPage.external?sp=422

20.04.2012