ABCMdb

PMID: 8522333

Desgeorges M, Rodier M, Piot M, Demaille J, Claustres M
Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype.
Hum Genet. 1995 Dec;96(6):717-20., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp Hum Genet (1995) 96:717-720 9 Springer-Verlag 1995 Marie Desgeorges 9 Michel Rodier 9 Michel Piot Jacques Demaille 9 Mireille Claustres Four adult patients with the missense mutation L206W and a mild cystic fibrosis phenotype Received: 28 February 1995 / Revised: 17 April 1995 Abstract We report molecular and clinical analyses in four unrelated patients with cystic fibrosis (CF) with compound heterozygosity for the L206W mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Login to comment 2 ABCC7 p.Leu206Trp On the basis of the clinical features presented by the four patients, we postulate that the L206W might be associated with pancreatic sufficiency and residual transmembrane transport of chloride in lung. Login to comment 10 ABCC7 p.Leu206Trp We had previously identified in our population one of the four missense mutations found in TM3, named L206W (Claustres et al. 1993). Login to comment 12 ABCC7 p.Leu206Trp As clinical and genetic analysis of CF patients help in our understanding of the genotype-phenotype relations and of the physiopathology of CF, we report the clinical features of four patients who were found to carry the putative mild mutation L206W. Login to comment 14 ABCC7 p.Leu206Trp Materials and methods Clinical report The genotypes and the main clinical features presented by the four patients heterozygous for L206W are summarized in Table 1. Login to comment 23 ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp At 22 years of age, Table 1 Clinical and laboratory features of individuals with L206W P S V A Ethnicity Andalusia Southern France Southern France Southern France Genotype G524X/L206W AI507/L206W AF508/L206W AFS08/L206W lntron 8 9T/9T 7T/9T 9T/9T 9T/gT Haplotype :' 6-B/g-B 6-D/8-B 6-B/8-B 6-B/8-B Sex Male Male Female Female Age at diagnosis 22 years 34 years 15 years 5 years Current age~' 29 years (1966) 40 years (1955) 17 years (1978) 15 years (1980) Professional activity Bricklayer Seasonal country worker Student Student Circumstances of Hypokaliemia, Hypokaliemia, DNA study Chronic bronchitis diagnosis diffuse muscle cramps, diffuse muscle cramps, extracellular depletion extracellular depletion Sweat chloride (mmol/l) 58, 78, 60 71, 58, 51 180, 200 60, 62 Meconium ileus No No No No Growth retardation No No Yes No Pancreatic sufficiency Yes Yes Yes Enzyme supplemented Respiratory function Normal course Repetitive upper airway Asthma, allergy Mild symptoms infections during infancy Other Azoospermia, Azoospermia, Obstructive uropathy, bilateral aplasia of vas bilateral aplasia of vas renal cyst (right) deferens deferens, alcoholism, nicotine addiction ~'6 or 8 is the number of (gatt) copies in intron 6a, B or D is the haplotype defined by the extragenic markers KM 19 and XV-2c h Birth date in parentheses Fig. 1 Structure of the families 1.206W studied. Login to comment 24 ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Gly542* ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp ABCC7 p.Leu206Trp Open symbols, and J~ 0 halJ:filled symbols, healthy individuals filled symbols, CF (cystic fibrosis) G542X G542X G542X G542X L206W 1.,206W AI507 S L206W L206W A1507 O L206W AF508 AF508 V #, g g g AF508 L206W L206W AF508 AF508 while working in the sun in the hot and arid climate of southern France, he presented with two severe acute dehydration episodes, with excessive sweating and salt crystals on the skin. Login to comment 41 ABCC7 p.Leu206Trp As L206W creates an StyI site, a simple PCR restriction test was designed to screen DNAs for this mutation: a site was not found among 100 non-CF alleles (data not shown). Login to comment 47 ABCC7 p.Leu206Trp Results and discussion In this paper we present four patients with the L206W mutation in one of their CFTR genes; this condition has not been described to date in other populations. Login to comment 48 ABCC7 p.Leu206Trp The missense mutation L206W replaces a leucine by a tryptophan residue at position 206 in exon 6a, in the middle of the third transmembrane domain (TM3) of the CFTR molecule. Login to comment 49 ABCC7 p.Leu206Trp Several arguments suggest that L206W is a CF allele and not a neutral sequence variation. Login to comment 53 ABCC7 p.Leu206Trp The study of DNA polymorphic sites revealed that, in each case, L206W is associated with haplotype 1-2-1-2-2 defined by the bi-allelic markers (XV2c-KM19-M470V- T854T-J.311), and with haplotype 16-7-17 defined by the three intragenic microsatellites (IVS8CA-IVS17BTA- IVS 17BCA). Login to comment 54 ABCC7 p.Leu206Trp Interestingly, L206W was found on a chromosome carrying eight copies of the (gatt) repeat in front of exon 6b; this has not been reported so far for other mutations. Login to comment 55 ABCC7 p.Leu206Trp Since L206W is associated with a 9T allele in intron 8, it can be deduced that exon 9 is correctly spliced into the corresponding CFTR mRNA (Kiesewetter et al. 1993). Login to comment 56 ABCC7 p.Leu206Trp In the light of previous studies on a genotype-phenotype correlation between CFTR mutations and pancreatic function in CF patients (Kristidis et al. 1992), the L206W mutation may be considered as a mild allele, as it confers a pancreatic sufficient phenotype to patients. Login to comment 58 ABCC7 p.Gly542* The alleles AF508 and AI507, located in NBD1, affect the processing of the CFTR, which fails to translocate to the correct cellular location at the apical membrane; the nonsense mutation G542X produces premature termination of translation, resulting in an unstable mRNA and no detectable protein (Welsh and Smith 1993). Login to comment 60 ABCC7 p.Leu206Trp Based on previous studies on missense mutations in the first membrane-spanning domain (Sheppard et al. 1993), it is tempting to speculate that L206W might affect the function of the channel pore, resulting only in a reduction of the amount of C1- current. Login to comment 61 ABCC7 p.Gly542* The CFTR protein with 206W might retain some residual function in respiratory and digestive tissues, exercising a "dominant" effect on the null alleles G542X, AI507 or AF508 and allowing the occurrence of mild phenotypes of CE In the two male patients reported here clinical expression of CF occurs only when the need for heat dissipation is tremendously increased and depends on evaporative heat loss. Login to comment