TWO CASES OF ALLELES WITH COMPLEX GENOTYPES AMONG CYSTIC FIBROSIS PATIENTS FROM CROATIA
Tanacković G1, Barišić I2, Knežević J1, Pavelić J1,*
*Corresponding Author: Professor Dr. Jasminka Pavelić, Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10002 Zagreb, Croatia; Tel: +385-1-4560-926; Fax: +385-1-456-1010; E-mail: jpavelic@rudjer.irb.hr
page: 3

DISCUSSION

Several literature reports have drawn the attention to the existence of CF alleles that carry, at the same time, the classical mutation and some of the polymorphic sites [3,4].

Both of our CF patients with alleles that have two genetic changes, have clear clinical features of disease. The one with genotype DF508/G542X+F508C has a milder form of CF, and the one with genotype DF508/ G542X+P1290P has a more severe form, accompanied by chronic airway infection. The first patient, with two genetic changes in exons that code for NBD1, had significantly higher sweat Cl– values than the second patient with the variations in the sequence for both NBDs (exons 10, 11 and 20) of the CFTR protein. These differences in the clinical feature of our patients could be result of the different genotypes, better to say different polymorphisms, considering that the mutations were the same in both cases. When sequence variations were in the part of the gene that code for the NBD1 domain (exons 9-12), clinical features were milder. A more severe clinical manifestation was present when exons for both NBD domains were mutated: exons 10 and 11 for NBD1 and exon 20 for NBD2. Thus, a deviation from a wild type of both NBD protein domains could be a reason for a more severe form of cystic fibrosis.

Considering that we found only one patient for each of the genotypes described, we cannot make certain conclusions. However, it would be interesting to combine our data with other scientists worldwide, and try to find answers about the influence of polymorphisms on the clinical features of CF patients.

 

 

 

Fig. 1. Detection of the G542X mutation. RFLP analysis (restriction enzyme MvaI) of polymerase chain reaction (PCR) products of exon 11 (3.5% agarose gel). Lane 1: molecular weight standard X (Boehringer Mannheim, Mannheim, Germany); lane 2: uncut PCR product (296 bp); lanes 3 and 5: control samples [homozygous wt/wt (wild type)]; lanes 4 and 6: heterozygous G542X/wt samples from patients 1 and 2, respectively.

 

 

 

      Fig. 2. DGGE for exon 10 of the CFTR gene from patient 1 (genotype DF508/G542+F508C) (30-60% denaturing polyacrylamide gel). Bands on the bottom of the gel are homoduplexes. Bands on the higher position in lanes 1 and 3 are heteroduplexes. Lane 1: control sample DF508/ wt; wt homoduplex upper band; lanes 2 and 4: control samples (homozygous DF508/DF508); lane 5: control sample (homozygous wild type); lane 3: patient’s DNA-complex allele G542X+F508C. Two homoduplex alleles correspond to DF508/DF508 (upper) and F508C/F508C (lower) mutations; a heteroduplex band (DF508/F508C) is also visible.

 

 

 

 

      Fig. 3. DGGE for exon 20 of CFTR gene for patient 2 (genotype DF508/G542X+P1290P) (20-70% denaturing polyacrylamide gel). An arrow indicates the heteroduplex bands, the lower bands are homoduplexes. Lane 1: control sample (P1290P/wt), lanes 2-7: DNA samples from our patients. Samples in lanes 2-6 are homozygous wt/wt. Sample in lane 7 is heterozygous P1290P/wt (double-mutant allele G542X+P1290P), that was indicated with the same homo- and heteroduplex bands as for the control sample in lane 1.

 




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