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Genotype-phenotype correlation in three homozygotes and nine compound heterozygotes for the cystic fibrosis mutation 2183AA→G shows a severe phenotype
  1. M O KILINÇ*,
  2. V N NINIS*,
  3. A TOLUN*,
  5. T CASALS,
  6. A SAVOV,
  7. E DAGLI§,
  8. F KARAKOǧ,
  10. G HÜNER,
  11. F ÖZKINAY**,
  12. E DEMIR**,
  13. J L SECULI††,
  14. J PENA‡‡,
  15. C BOUSONO§§,
  17. C CALVO***,
  18. G GLOVER†††,
  19. I KREMENSKI‡‡‡
  1. * Department of Molecular Biology and Genetics, Bogaziçi University, Bebek 80815 Istanbul, Turkey
  2. Genetics Department, IRO, Barcelona, Spain
  3. Laboratory of Molecular Pathology, University Obstetrics and Gynecology Hospital, Sofia, Bulgaria
  4. § Pediatrics, Marmara University Hospital, Istanbul, Turkey
  5. Nutrition and Metabolic Disorders Division, Istanbul University Medical School, Istanbul, Turkey
  6. ** Pediatrics, Aegean University Medical School, Izmir, Turkey
  7. †† Cystic Fibrosis Unit, Pediatrics Service, Hospital S Juan Deu, Barcelona, Spain
  8. ‡‡ Pediatric Service, Hospital General, Santiago Compostela, Spain
  9. §§ Pediatric Service, Hospital Central, Oviedo, Spain
  10. ¶¶ Gastroenterology Service, Hospital La Fe, Valencia, Spain
  11. *** Pediatric Service, Hospital Clinico, Valladolid, Spain
  12. 169 ††† Centro Bioquimica Espinardo, Murcia, Spain
  13. ‡‡‡ Laboratory of Molecular Pathology, Medical University, Sofia, Bulgaria
  1. Dr Tolun, tolun{at}

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Editor—Cystic fibrosis (CF) is the most common lethal childhood disorder in white populations and occurs at a frequency of about 1/2500 with regional variations. Over 1000 mutations in the CF transmembrane conductance regulator (CFTR) gene accounting for the disease have been identified so far and the most common gene mutation is ΔF508.1 The frameshift mutation 2183AA→G in exon 13 was first described in three Canadian CF patients2 and later was shown to have a significant frequency in patients from mid and southern Europe. The frequency among CF patients is 9.3% in north east Italy,3 2.4% in the Tyrol,4 1-2.1% in Belgium,3 1.8% in Greece,5 1% in Bavaria, Bulgaria, and France,3 and 0.4% in mid and northern Germany.6 We identified three homozygotes among 120 Turkish patients (2.5%), two born to first cousin parents, three compound heterozygotes among 185 Bulgarian patients (0.8%), and seven compound heterozygotes among 650 Spanish patients (0.5%).7 The mutation was detected by denaturing gradient gel electrophoresis or single strand conformational analysis followed by DNA sequence analysis.

We report here the genotype-phenotype correlation in 12 patients with CF with the mutation 2183AA→G (three homozygous and nine compound heterozygous for 2183AA→G and other mutations). The anamnestic, clinical, and laboratory data are summarised in table 1. Pancreatic insufficiency (PI) was assessed by the fat content of stools and requirement of pancreatic enzyme replacement therapy. Gastrointestinal symptoms (GI) are abdominal cramps and pain and frequent passage of foul and fatty faeces. The presence of pulmonary symptoms was defined as having at least one of the following clinical findings: increased rate of breathing, wheezing, dark coloured/profuse sputum, and recurrent attacks of coughing. Dehydration includes at least one of the following: decreased skin tonus and turgor, decreased output of urine, and sudden weight loss. The presence of bronchiectasis was evaluated by chest x rays and thin section computerised chest tomography.

Table 1

Anamnestic, clinical, and laboratory data for CF patients carrying the mutation 2183AA→G

Patient 1 was homozygous for 2183AA→G. She was admitted to hospital at 2 months of age and died within a week. Clinical findings were clearly of CF with pancreatic insufficiency. The second homozygous patient (patient 2) was examined for CF because all his four sibs had died of the disease before the age of 1 year. He had pulmonary insufficiency at 15 days. He had fatty and foul stools, bronchial hyperactivity, and early Pseudomonascolonisation. As a result of medical treatment, he no longer has steatorrhoea or Pseudomonas infection. The third homozygous patient (patient 3) was diagnosed early because his brother died of similar clinical findings at the age of 10 months. The clinical symptoms were gastrointestinal and pulmonary; in addition, vitamin deficiency, malnutrition, and severe anaemia (probably resulting from severe vitamin A deficiency) were observed. At present, he has early Pseudomonas colonisation, steatorrhoea, recurrent lung problems, and malnutrition.

The remaining nine patients are all compound heterozygotes. Patients 4-8 carry ΔF508 as the other CF allele. Patients 4 and 7 were diagnosed with meconium ileus. Other clinical data available for patient 4 are malnutrition, chronic respiratory insufficiency, and steatorrhoea. Patient 7 also has β thalassaemia. Patient 8 has bronchiectasis. Patients 9 and 10 carry the nonsense mutation G542X8 on the other CFTR chromosome. Patient 9 has hepatomegaly, probably resulting from nutritional deficiency. Patient 10 was first diagnosed as having coeliac disease, then CF as well, and also has anorexia. Patient 11 carried the missense mutation G1244E9 on the other CFTR chromosome. Pancreatic insufficiency was confirmed by a fat load test, which showed a poor rise in the plasma triglyceride level and an excretion of 60 mmol/day (normal is 20 mmol/day). An ultrasound examination of the liver showed a normal sized liver with markedly increased echogenicity, suggesting hepatic involvement. The enlarged portal vein had a diameter of 12 mm and the spleen and kidneys were normal. A chest radiograph showed widespread peribronchial thickening with interstitial markings, but there were no areas of atelectasis, and in general the changes were not severe. Two years later the chest radiograph showed a quite marked deterioration with much more widespread bronchiectatic changes. Patient 12 has 2789+5G→A, a splice site mutation,10 on the other CFTR chromosome. She has recurrent respiratory infections.

The mutation 2183AA→G causes premature termination of translation 38 codons downstream on exon 13. The clinical data presented for three patients homozygous for the mutation and eight compound heterozygous patients who carry a severe mutation (ΔF508, G542X, and G1244E) on the other CFTR chromosome indicate that the mutation causes a severe CF phenotype. Severe pancreatic insufficiency is the most common clinical feature, being exhibited by all these 11 patients. Pancreatic insufficiency had also been reported for all three Canadian compound heterozygous patients.2 Current moderate progression of the disease in some of these patients is probably the result of treatment with pancreatic enzyme supplements and antibiotics. The disease phenotype is also severe in the compound heterozygote with the mutation 2789+5G→A. It has been shown that this mutation has a mild phenotype which allows synthesis of some normal mRNA.10

The phenotype of the mutation 2183AA→G was assessed to be severe with pancreatic involvement, failure to thrive, and variable lung involvement (9/12 patients). In 5/10, colonisation with bacterial pathogens was observed. Two patients died too young (1-2 months) for bacterial colonisation to be assessed. Two of the ΔF508/2183AA→G patients had meconium ileus. The mutation may cause various other complications, with two patients exhibiting hepatic involvement and two bronchiectasis. All patients studied were diagnosed very early. Grouping the patients and their sibs together, six homozygotes died within the first year of life and two compound heterozygotes died at the ages of 1 month and 12 years.

In most of our heterozygous patients, theCFTR gene was only partially screened for mutations using either DGGE or SSCP. Thus, it is possible but unlikely that some of these patients carry a third CF mutation. Spanish and Turkish patients were analysed for the IVS8-6(T) alleles11and the mutation 2183AA→G was found to be associated with the allele 7T, except in patients 1 and 3, who were homozygous for the allele 9T. Spanish and Turkish patients were also studied for the microsatellite loci IVS8CA, IVS17bTA, and IVS17bCA.12-14 While all six Spanish patients shared the same haplotype (16-30-13) for the mutation 2183AA→G, Turkish patients were homozygous for two other haplotypes, 16-31-13 (patients 1 and 3) and 16-32-13 (patient 2). These three haplotypes are among the most common on normal chromosomes15 and each can be derived from any of the other two. Alternatively, the mutation may have arisen independently in the two populations or even within the Turkish population. Despite the possible heterogeneous genetic background observed, in particular between the homozygous patients, the severity of the disease is similar.


The authors thank the European Community Concerted Action for the Coordination of Cystic Fibrosis Research and Therapy for providing the DGGE and sequencing oligonucleotide primers for the analysis of Spanish and Turkish patients. The work on Spanish patients was supported by FISS 96/2005 and Institut Catala de la Salut. The work on Turkish patients was supported by the Scientific and Technical Research Council of Turkey, The Academy of Sciences of Turkey, and Bogaziçi University Research Fund.


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