Deletion ΔF508 and haplotype analysis of CFTR gene region in Slovak CF patients

Summary Analysis of a sample of 50 unrelated cystic fibrosis (CF) patients and 46 nuclear families from Slovakia (Czechoslovakia) by the polymerase chain reaction and Southern hybridization revealed that the proportion of the F508 mutation was 58% in this population, and that the frequency of the B (i.e., KM19/XV2c [1–2]) haplotype was increased in both F508 and nonF508 CF chromosomes (98% and 46%, respectively). These results support the view that the trans-European gradient of the F508 frequency is of a geographical rather than of an ethnic origin, and that in Slavonic populations, there exists an as yet unidentified but frequent CF mutation other than F508, associated with the B haplotype.     

Cystic fibrosis in Spain: high frequency of mutation G542X in the Mediterranean coastal area

We have determined the frequency of deletion F508 and mutation G542X, a nonsense mutation in exon 11 of the cystic fibrosis (CF) gene, in a sample of 400 Spanish CF families. Mutation G542X represents 8% of the total number of CF mutations in Spain, making it the second most common mutation after the F508 deletion, which accounts for 48% of CF chromosomes. G542X has a higher frequency in the Mediterranean coastal area (14%) and in the Canary Islands (25%). About 70% of G542X chromosomes are from Andalucia, Múrcia, Valencia, Catalunya and the Canary Islands. The F508 deletion has its highest frequency in the Basque Country (83%). Mutation G542X is associated with the same rare haplotype that is found in association with the F508 mutation. The haplotype homogeneity found for G542X, even when intragenic microsatellites (IVS8CA, IVS17BTA and IVS17BCA) are considered, allows us to postulate that this mutation arose from a single mutational event. The geographic distribution of mutations F508 and G542X suggests that F508 was present in the Iberian Peninsula before the Indo-European invasions, and that G542X was introduced into Spain, via the Mediterranean Sea, probably by the Phoenicians, between 2500 and 3000 years ago.     

Molecular analysis of cystic fibrosis in the Hungarian population

Summary Hungarian cystic fibrosis (CF) families (n = 33) including 114 family members have been analysed for the presence of the F508 mutation within the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and have been haplotyped with probes for restriction fragment length polymorphisms (RFLPs) known to be linked to the CFTR gene. The F508 deletion was present in 64% of CF chromosomes. As in many other populations, linkage disequilibrium was found between the CF locus and the haplotype B (XV-2c: allele 1, KM1-9: allele 2), which accounts for 95% of F508 CF chromosomes in our families.     

The occurrence of various non-ΔF508 CFTR gene mutations among Hungarian cystic fibrosis patients

Summary Cystic fibrosis (CF) is an autosomal recessive disease caused by different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The frequency of the major mutation (F508) in the Hungarian population is 64%. To identify other common mutations in CF families from Hungary, 30 nonF508 CF chromosomes were analyzed for selected mutations in exon 11 (G551D, R553X, G542X), intron 4 (621+1GT), intron 10 (1717–1GA), exon 20 (W1282X), and in exon 21 (N1303K) of the CFTR gene. In 6 of the 30 non-F508 CF chromosomes the following mutations were detected: R553X, G542X, 1717–1GA, W1282X, and N1303K. After analysis of the above eight mutations, 30% of CF chromosomes are as yet undefined and further analysis is planned.     

Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene

Summary Three mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were discovered in a pancreas-insufficient patient with cystic fibrosis (CF) who displayed an uncommon combination of almost normal chloride concentration in sweat tests and typical symptoms of gastrointestinal and pulmonary disease. The R553Q mutation was found on the maternal F508-CFTR gene. Codon 553 is located within a consensus motif of the ATP-binding cassette transport proteins at a less conserved position. Other members of this protein superfamily contain a glutamine instead of arginine at the homologous position, suggesting a modulating rather than disease-causing role of the R553Q mutation in CFTR. The amplification refractory mutation system did not detect the R553Q mutation in a further 65 normal, 113 F508, and 91 non-F508 CF chromosomes. The index case carried the R553X nonsense mutation on the paternal chromosome. The R553X mutation was present on a further 9 out of 86 German nonF508 CF chromosomes linked with the XV2c-KM19Mp6d9-J44-GATT haplotypes 2-2-2-1-1 and 1-1-2-1-2. The location of R553X on separate haplotypes including both alleles of the intragenic GATT repeat suggests an ancient and/or multiple origins of the R553X mutations. The association of the genotype of the CFTR mutation and the clinical phenotype was assessed for the patients carrying the related genotypes F508/F508 (n = 80), F508/R553X (n = 9) and F508-R553Q/R553X (n = 1). In compound heterozygotes, the median chloride concentration in pilocarpine iontophoresis sweat tests was significantly lower than in the F508 homozygotes (P < 0.01). The patient groups were significantly different with respect to the distributions of the centiles for height (P < 0.001) and weight (P < 0.01) as the most sensitive predictors of the course and prognosis in CF. Growth retardation was more pronounced in the compound heterozygotes.     

Average phase difference theory and 1∶1 phase entrainment in interlimb coordination

The dynamics of coupled biological oscillators can be modeled by averaging the effects of coupling over each oscillatory cycle so that the coupling depends on the phase difference between the two oscillators and not on their specific states. Average phase difference theory claims that mode locking phenomena can be predicted by the average effects of the coupling influences. As a starting point for both empirical and theoretical investigations, Rand et al. (1988) have proposed d/dt= — K sin ), with phase-locked solutions =arcsin( /K), where is the difference between the uncoupled frequencies and K is the coupling strength. Phase-locking was evaluated in three experiments using an interlimb coordination paradigm in which a person oscillates hand-held pendulums. was controlled through length differences in the left and right pendulums. The coupled frequency _c was varied by a metronome, and scaled to the eigenfrequency _v of the coupled system K was assumed to vary inversely with _c. The results indicate that: (1) and K contribute multiplicatively to (2) =0 or = regardless of K when =0; (3) 0 or regardless of when K is large (relative to ); (4) results (1) to (3) hold identically for both in phase and antiphase coordination. The results also indicate that the relevant frequency is _c/_v rather than _c. Discussion high-lighted the significance of confirming =arcsin(/K) for more general treatments of phase-locking, such as circle map dynamics, and for the 11 phase-entrainment which characterizes biological movement systems.     

Characterisation and transferability of apple SSRs to two European pear F<Subscript>1</Subscript> populations

European pear (Pyrus communis L.) is among the important fruit species for which only few genetic studies have been carried out. Available evidence indicates that simple sequence repeats (SSR) are very useful as molecular markers because they are codominant, highly polymorphic, abundant and reproducible. The present paper reports more than 100 apple SSR markers in two populations of European pear; a total of 41 SSR markers were then positioned on a genetic linkage map of the cross Passe Crassane × Harrow Sweet and 31 in the map Abbè Fétel × Max Red Bartlett. Syntenic relationships between pear and apple maps have been considered for the chromosomes carrying two or more SSR markers. The alignment among the two maps supports the colinearity of the two genomes with respect both to identification and to orientation of the linkage groups.     

Anaerobic biosynthesis of unsaturated fatty acids in the cyanobacterium,Oscillatoria limnetica

The mechanism for synthesis of monounsaturated fatty acids under aerobic and anaerobic conditions was studied in the facultative anaerobic cyanobacterium, Oscillatoria limnetica. The hexadecenoic acid (C161) of aerobically grown O. limnetica was shown to contain both the 7 (79%) and 9 (21%) isomers, while the octadecenoic (C181) acid was entirely the 9 acid. Incorporation of [2-¹⁴C] acetate into the fatty acids under aerobic conditions resulted in synthesis of the 7 and 9 C161 and the 9 C181. Synthesis of unsaturated fatty acids in the presence of DCMU required sulfide. Anaerobic incubations in the presence of DCMU and sulfide (less than 0.003% atmospheric oxygen) resulted in a two-fold increase in monounsaturated fatty acids of both 7 and 9 C161 and 9 and 11 C181. The synthesis of these isomers is characteristic of a bacterialtype, anaerobic pathway.Abbreviations DCMU 3(3,4-dichlorophenyl)-1,1-dimethylurea - MFA monounsaturated fatty acid     

Frequency of the F508 deletion in cystic fibrosis patients from the European part of the USSR

Summary The frequency of the F508 deletion (F508) has been analyzed in 189 cystic fibrosis (CF) patients from the European part of the USSR, viz. 127 nothern Slavonians (Leningrad region), 30 southern Slavonians (the Ukraine), 10 central Slavonians (Moscow region), 14 Moldavians (Kishenev region) and 8 Lithuanians (Vilnius region). The distribution of CF⁺ chromosomes with and without F508 varied significantly in the different ethnic groups studied and correlated with the clinical manifestation of CF. The overall frequency of F508 in Slavonian patients is equal to 62.5%, approximately 90% of them being heterozygous or homozygous for this mutation. The frequency of the deletion among 99 Slavonian patients with severe disease manifestation (pancreatic insufficiency, PI) is equal to 67.5%, only 12 patients having pancreatic sufficiency (PS, 17.5%). The highest value of F508 (77.4%) is registered in PI/CF patients of the southern Slavonian group; it is much less frequent (about 57%) in relevant groups of Slavonians from the northern and central parts of the country. Unusually low frequencies (24% and 26%) of F508 are detected in a few samples of Lithuanian and Moldavian CF patients, respectively. All F508⁺CF-chromosomes of Slavonian origin are associated with haplotypes 2.2.2. defined by the restriction fragment length polymorphism sites KM19/PstI, CS.7/Hin6I and MP6d-9/MspI, although a high proportion (about 25%) of unknown mutations is associated with the same haplotype. Haplotype B (allele 1XV2c/TaqI; allele 2 KM19/PstI) accounts for 91% of F508⁺CF chromosomes. Our data are consistent with the hypothesis of a single origin and subsequent diffusion of this major CF mutation; however, its interpopulational dissemination in Eastern Europe does not follow the suggested south-east to north-west gradient in Western Europe. The significance of these data for prenatal diagnosis and carrier screening of CF mutations is briefly discussed.     

Effect of axoplasmic transport blockade on end-plate currents in frog muscle fibers

Evoked and spontaneous end-plate currents (EPC) were studied in normal voltage-clamped frog sartorius muscle fibers and 2 weeks after application of colchicine to the nerve innervating the muscle to block axoplasmic transport in its fibers. Application of colchicine was found to reduce the rate of rise and to prolong decay of EPC without affecting the amplitude of the EPC and miniature EPC, the quantum composition of EPC, and the frequency of miniature EPC. The histogram of distribution of the time constant () of EPC decay under normal conditions follows the normal law, but after application of colchicine to the nerve it is shifted to the right, with separation of two modes (₁ and ₂). Three types of synapses can be distinguished from the character of EPC decay: monoexponential decay with ₁ (44%), biexponential decay with ₁ and ₂ (39%), and monoexponential decay with ₂ (19%). An increase in of EPC decay is accompanied by strengthening of the dependence of this process on the clamping voltage. The current-voltage characteristic and reversal potential of EPC are unchanged. It is suggested that the change in character of EPC decay after application of colchicine to the motor nerve is due to the appearance of acetylcholine-activated ionic channels in the muscle membrane with a longer duration of the open state and with potential-dependence of the open state similar to that taking place after muscle denervation.S. V. Kurashov Medical Institute, Ministry of Health of the RSFSR, Kazan'. Translated from Neirofiziologiya, Vol. 17, No. 2, pp. 204–211, March–April, 1985.     

Cystic fibrosis in a low-incidence population: two major mutations in Finland

The incidence of cystic fibrosis (CF) in Finland, 125 000 newborn, is one of the lowest in Caucasian populations. The F508 mutation accounts for 18/40 (45%) of CF chromosomes in Finland. Other mutations were therefore sought among the remaining 55%. Twelve out of 40 chromosomes (30%) were found to carry 394delTT, whereas G542X and 3732delA were each detected in one chromosome. Eight mutations remained unidentified using a testing panel for 26 mutations. Mutation 394delTT was associated exclusively with haplotype 23-36-13. Five unknown mutations were associated with different haplotypes for microsatellite markers, whereas three shared the same haplotype. Most F508 mutations and all unidentified mutations originated from regions of old and dense settlement in the coastal regions, whereas 394delTT was geographically clustered and enriched in a rural location, consistent with a local founder effect. The remote location of Finland and her population history give a plausible explanation for the rarity of CF in Finland.     

Protonmotive force in Brevibacterium flavum: the lack of intracellular pH homeostasis

Brevibacterium flavum 22LD-P cells were shown to maintain a transmembrane pH gradient (pH) from 0.6 to 1.8–2 units and a transmembrane electric potential difference () from 0 to 200 mV depending on the pH and ionic composition of the incubation medium, grwoth substrate and concentration of cells. decreased from 120–140 mV to 0 when medium pH was lowered from neutral to 5.0–5.5 and increased to 180–200 mV when medium pH was raised to 8–9 in cells utilizing acetate or endogenous substrate. Cells growing on sucrose, kept around 100–120 mV at neutral as well as acidic medium pH. Intracellular pH in the acetate utilizing or endogenously respiring cells was maintained with the range of 8.9 to 5.5 at medium pH ranging from 9.1 to 4.0, respectively. Sucrose grown cells were able to maintain a more stable intracellular pH. Endogenously respiring cells in potassium phosphate buffer at high biomass concentrations maintained larger pH and relatively smaller , than the same cells in diluted suspensions. Cells in sodium phosphate buffer possessed larger and almost no pH, but was still dependent on biomass concentration.The lack of intracellular pH homeostasis and the collapse of at acid medium pH are discussed in the context of cell membrane proton permeability.     

Ethnocentricity and the social construction of ‘mass hysteria’

This study provides a critical historical review and analysis of the variety of human expressions which have been erroneously labeled under the grandiose category mass hysteria. It is argued that Western science reductionist approaches to the classification of mass hysteria treat it as an entity to be discovered transculturally, and in their self-fulfilling search for universals systematically exclude what does not fit within the autonomous parameters of its Western-biased culture model, exemplifying what Kleinman (1977) terms a category fallacy. As a result of objectivist methodologies, the etiology of actions labeled as mass hysteria is typically viewed as deviant, irrational or abnormal behavior resulting from a malfunctioning proper social order. However, what constitutes the correct social order is a function of a researcher's historical sociocultural and/or scientific milieu. This study reviews the problem, advocating Geertz's (1973) culturally relativistic approach to understanding various cross-cultural behavior that is sensitive to and tolerant of the unique context and milieu of participants. Mass or epidemic hysteria is viewed as an invention of Western psychiatry and should be abandoned and replaced with the term collective exaggerated emotions. Instead of attempting to discover a neatly packaged, unitary external disease entity, the focus of a meaning-oriented approach emphasizes the deciphering of foreign realities, semantic networks and symbol systems.     

The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update

Mitochondrial dysfunction has been shown to participate in the induction of apoptosis and has even been suggested to be central to the apoptotic pathway. Indeed, opening of the mitochondrial permeability transition pore has been demonstrated to induce depolarization of the transmembrane potential (_m), release of apoptogenic factors and loss of oxidative phosphorylation. In some apoptotic systems, loss of _m may be an early event in the apoptotic process. However, there are emerging data suggesting that, depending on the model of apoptosis, the loss of _m may not be an early requirement for apoptosis, but on the contrary may be a consequence of the apoptotic-signaling pathway. Furthermore, to add to these conflicting data, loss of _m has been demonstrated to not be required for cytochrome c release, whereas release of apoptosis inducing factor AIF is dependent upon disruption of _m early in the apoptotic pathway. Together, the existing literature suggests that depending on the cell system under investigation and the apoptotic stimuli used, dissipation of _m may or may not be an early event in the apoptotic pathway. Discrepancies in this area of apoptosis research may be attributed to the fluorochromes used to detect _m. Differential degrees of sensitivity of these fluorochromes exist, and there are also important factors that contribute to their ability to accurately discriminate changes in _m.     

Relationship of the Donnan potential to the transmembrane pH gradient in tracheal apical membrane vesicles

Summary Experiments were performed to determine the factors which contribute to the transmembrane pH gradient (pH) and the potential gradient () in apical plasma membrane vesicles isolated from bovine tracheal epithelium. As indicated by the accumulation of¹⁴C-methylamine, the vesicles maintained a pH (inside acidic) which was dependent upon the external pH. The pH was also proportional to the ionic strength of the suspending medium, suggesting that the H⁺ distribution was dictated by a Donnan potential. Measurements of the distribution of⁸⁶Rb⁺ demonstrated an electrical potential gradient across the vesicle membrane, inside negative which was proportional to the medium ionic strength. pH changed in parallel with in response to a variety of imposed conditions. These results are compatible with the existence of a H⁺ conductance in the vesicle membrane. Thus the endogenous electrical and proton gradients may be manipulated and used as a general experimental tool to complement kinetic analysis in investigations of transport mechanism using isolated vesicle preparations.     

Cytogenetic analysis of structural rearrangements in three varieties of common wheat,Triticum aestivum

Summary The winter wheat varieties Starke and Cappelle Desprez and the spring wheat Chinese Spring were analysed for structural chromosome rearrangements that resulted in the formation of multivalents in F₁ hybrids. The analyses were carried out using hybrids involving euploids, monosomic and ditelosomic stocks, and double-monotelodisomic constructs. The study confirmed that Cappelle Desprez differs from Chinese Spring in a reciprocal translocation between chromosomes 5B and 7B (Riley et al. 1967); a translocation involving chromosomes 3B and 3D could not be verified. Furthermore, the analysis showed that Starke differs from Chinese Spring in a reciprocal translocation between chromosomes 7A and 7D. Both translocations have a coefficient of multivalent realisation of about 0.84. Further multivalents in euploid Starke, in euploid and some aneuploid stocks of Cappelle Desprez, and in euploid as well as various types of aneuploid hybrids between all three varieties could nearly all be explained hypothesizing that chromosome 2B of both Starke and Cappelle Desprez is a duplication-deficiency chromosome. In the hypothesis a part of the long arm of 2B is missing and replaced by a duplicated part of the long arm of chromosome 2D. The multivalents of this rearrangement showed an average coefficient of realisation of about 0.09.Sven Ellerström died in December 1985     

Negative-ion fast atom bombardment tandem mass spectrometry for characterization of sulfated unsaturated disaccharides from heparin and heparan sulfate

Negative-ion fast atom bombardment tandem mass spectrometry has been used in the characterization of non-, mono-, di- and trisulfated disaccharides from heparin and heparan sulfate. The positional isomers of the sulfate group of monosulfated disaccharides were distinguished from each other by negative-ion fast atom bombardment tandem mass spectra, which provide an easy way of identifying the positional isomers. This fast atom bombardment collision induced dissociation mass spectrometry/mass spectrometry technique was also applied successfully to the characterization of di- and trisulfated disaccharides.Abbreviations FABMS fast atom bombardment mass spectrometry - CID collision induced dissociation - MIKE mass analysed ion kinetic energy - MS/MS mass spectrometry/mass spectrometry - HPLC high performance liquid chromatography - UA d-gluco-4-enepyranosyluronic acid - CS chondroitin sulfate - DS dermatan sulfate - HA hyaluronan - Hep heparin - HS heparan sulfate - UA(14) GlcNAc 2-acetamido-2-deoxy-4-O-(-d-gluco-4-enepyranosyluronic acid)-d-glucose - UA(14)GlcNAc6S 2-acetamido-2-deoxy-4-O-(-d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-glucose - UA2S(14)GlcNAc 2-acetamido-2-deoxy-4-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-d-glucose - UA2S(14)GlcNAc6S 2-acetamido-2-deoxy-4-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-glucose - UA(14)GlcN6S 2-amino-2-deoxy-4-O-(-d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-glucose - UA2S(14)GlcN 2-amino-2-deoxy-4-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-d-glucose - UA2S(14)GlcN6S 2-amino-2-deoxy-4-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-glucose - UA(14)GlcNS 2-deoxy-2-sulfamino-4-O-(-d-gluco-4-enepyranosyluronic acid)-d-glucose - UA(14)GlcNS6S 2-deoxy-2-sulfamino-4-O-(-d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-glucose - UA2S(14)GlcNS 2-deoxy-2-sulfamino-4-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-d-glucose - UA2S(14)GlcNS6S 2-deoxy-2-sulfamino-4-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-glucose - UA(13)GalNAc 2-acetamido-2-deoxy-3-O-(-d-Gluco-4-enepyranosyluronic acid)-d-galatose - UA(13)GalNAc4S 2-acetamido-2-deoxy-3-O-(-d-gluco-4-enepyranosyluronic acid)-4-O-sulfo-d-galactose - UA(13)GalNAc6S 2-acetamido-2-deoxy-3-O-(-d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-galactose - UA2S(13)GalNAc 2-acetamido-2-deoxy-3-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-d-galactose - UA2S(13)GalNAc4S 2-acetamido-2-deoxy-3-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-4-O-sulfo-d-galactose - UA2S(13)GalNAc6S 2-acetamido-2-deoxy-3-O-(2-O-sulfo--d-gluco-4-enepyranosyluronic acid)-6-O-sulfo-d-galactose - UA(13)GalNAcDiS 2-acetamido-2-deoxy-3-O-(-d-gluco-4-enepyranosyluronic acid)-4,6-di-O-sulfo-d-galactose - UA(13)GlcNAc 2-acetamido-2-deoxy-3-O-(-d-gluco-4-enepyranosyluronic acid)-d-glucose.     

Meiosis and fertility of F1 hybrids between hexaploid bread wheat and decaploid tall wheatgrass (Thinopyrum ponticum)

As the first step in the transfer of barely yellow dwarf virus resistance and salt tolerance from decaploid tall wheatgrass (Thinopyrum ponticum) into hexaploid bread wheat (Triticum aestivum L.), octoploid intergeneric hybrids (2n = 8x = 56) were synthesized by crossing the tall wheatgrass cultivar Alkar with wheat cvs. Fukuhokomugi (Fuko) and Chinese Spring. (Fuko x Alkar) F₁ hybrids were studied in detail. The F₁ hybrids were perennial and generally resembled the male wheatgrass parent with regard to morphological features and gliadin profile. Most hybrids were euploid with 56 chromosomes and showed high chromosome pairing. On an average, in 6 hybrids 83.6% of the complement showed chiasmatic association, some between wheat and wheatgrass chromosomes. Such a high homoeologous pairing would be obtained if Ph1, the major homoeologous pairing suppressor in wheat, was somehow inactivated. Some of the Fuko x Alkar hybrids had high pollen fertility (18.5–42.0% with a mean of 31.5%) and high seed fertility (3–29 seeds wtih a mean of 12.3 seeds per spike), offering excellent opportunities for their direct backcrossing onto the wheat parent.     

Analysis of the 5′ flanking sequence of the Gγ globin gene by denaturing gradient gel electrophoresis confirms the heterogeneity of the Bantu βs haplotype

Summary The GCTT polymorphism recently described at positions — 1106 and — 1105 in the 5 flanking region of the G globin gene for the Bantu ^S haplotype was analysed by denaturing gradient gel electrophoresis. We studied 108 ^S chromosome and 122 ^A chromosomes. The TT sequence was found as follows: in all of 80 chromosomes bearing the Bantu ^S haplotype with the 6-bp deletion -400 nt from the G gene in 3 out of 5 Bantu ^S chromosomes without the deletion, in 1 out of 122 ^A chromosomes from different ethnic origins but in none of 23 ^S chromosomes bearing the Senegal, Benin or Cameroon haplotypes. These results confirm the heterogeneity of the Bantu ^S haplotype and allow a tentative evolutionary sequence for the different alleles at this locus to be presented.     

Clinical characteristics of 16 cystic fibrosis patients with the missense mutation R334W,a pancreatic insufficiency mutation with variable age of onset and interfamilial clinical differences

We present the genotype/phenotype correlation analysis for 16 cystic fibrosis (CF) patients who carry mutation R334W. Current age and age of diagnosis was significantly higher in the R334W/any-mutation group (P < 0.05 and P < 0.01), compared with the 508/508 group. A slightly, but not significantly, worse lung function was found in the R334W/any-mutation group, when compared with the 508/508 patients. The proportion of patients with lung colonization with bacterial pathogens was slightly, but not significantly, higher in the R334W/any-mutation group (71.4%), compared with the 508/508 or R334W/508 groups (55.5%). None of the R334W patients had meconium ileus but 60% were pancreatic insufficient (PI), a significantly lower proportion (P 0.001) than 508/508 patients. Two R334W/N1303K compound heterozygous sisters were PI but discrepant for lung function. Two groups of three sibs with genotype R334W/508 showed interfamilial discordant clinical data for lung and pancreatic function. The data provided here for mutation R334W demonstrate that this mutation is responsible for a less severe form of CF than 508. Interfamilial differences for PI and lung function suggest that other factors, viz. genetic, environmental and medical, contribute to the wide spectrum of clinical differences observed in CF patients with the same CF transmembrane conductance regulator genotypes.