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Cystic fibrosis caused by homozygosity for the CFTR gene mutation 175insT

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene resulting in deficiency of the corresponding membrane protein, a regulated chloride channel (1). The commonest mutation, AF508, is believed to have originated as a single event, perhaps thousands of years ago (2). However, more than 500 mutations are on record (3), most of which are rare or have been found only in single cases. Such events may be de novo mutations of recent date, occurring in the patient or one of the patient's parents. No study of C F has been published where an extensive examination has been made of several generations. The 175insT mutation has previously been found, in a heterozygous form, in only one case, a patient of Danish origin, who carried AF508 on the other allele (4). We describe how this rare mutation, appearing in a homozygous form in two patients, could be traced back to the middle of the 19th century. Patient 1 was a 5-year-old girl diagnosed as having C F at 3 years of age after a period of recurrent pneumonia and weight loss. Sweat chloride values were 94-105 mmol/l. Clinically, she had moderatesevere lung disease, pancreatic insufficiency and chronic Pseudomonas aeruginosa colonization. Patient 2 was a 15-year-old boy diagnosed as having C F at 5 years of age after some years of daily coughing, recurrent pneumonia and, just prior to diagnosis, weight loss. Sweat chloride value was 86 mmol/l. Lung function tests indicated moderate-severe pulmonary disease with a VC of 80% and an FEVl 35% of normal. He was chronically colonized with Pseudomonas aeruginosa and had pancreatic insufficiency. The patient had clinical symptoms of vitamin E deficiency with polyneuropathy. He also had osteoporosis. Exons of the CFTR gene were amplified using oligonucleotide primers, as described previously (5), one primer in each pair being biotinylated. Sequencing was done with the dideoxy method using the Dynal streptavidin bead system. The XV2C and KM19 haplotypes were analysed as described previously (6). Analyses of the microsatellites CAIVS 8, CAIVS17, TAIVS 17 and the polymorphic TTGA repeats in intron 6A were performed as reported previously (7, 8). Genealogical studies were based on information obtained from parish registry records, county records offices and family members. Figure 1 shows the insertion of thymine (T) at nucleotide position 175 in exon 1 (left) and a normal sequence (right). This insertion was found in a homozygous form in both patients (NosV1:l and VI:2 in Fig. 2). The mutation results in a frameshift with a termination codon at nucleotide 260 in exon 2. Table 1 shows the CFTR gene haplotypes of the two patients and the previously reported Danish patient with the 175insT mutation in a heterozygous form. This illustrates that the haplotype background differs between the Danish and the two Swedish patients, indicating separate origins of the mutation. Figure 2 shows the results of the family studies. The pedigree covers six generations. The woman in generation I was born in 1859, and the father of II:3 is reported to be unknown. The two patients in generation VI are homozygous for 175insT as a result of multiple consanguineous marriages. Homozygosity for one and the same C F allele is rare, except for AF508, and, in Ashkenazi Jews, W1282X (9). The present report describes the clinical picture in two related C F patients who were homozygous for the CFTR gene mutation, 175insT. Both manifested the full-blown CF phenotype with respect to lung disease