Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians

Uppaluri, L.; England, S. J.; Scanlin, Thomas F.

doi:10.1016/j.jcf.2012.02.001

Cited by 9 publications

(12 citation statements)

References 14 publications

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“…ystic fibrosis (CF) is a fatal inherited disease that is common among the Caucasian population and affects 30,000 and 3,000 newborns/year in the United States and Canada, respectively (1,2). Cystic fibrosis is a multiorgan disease affecting the liver, pancreas, gastrointestinal tract, and lungs; however, pulmonary injury is the main cause of death among CF patients (3)(4)(5).…”

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confidence: 99%

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Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Alhajlan

Alhariri

Omri

2013

Antimicrob Agents Chemother

116

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We investigated the efficacy and safety of liposomal clarithromycin formulations with different surface charges against clinical isolates of Pseudomonas aeruginosa from the lungs of cystic fibrosis (CF) patients. The liposomal clarithromycin formulations were prepared by the dehydration-rehydration method, and their sizes were measured using the dynamic-light-scattering technique. Encapsulation efficiency was determined by microbiological assay, and the stabilities of the formulations in biological fluid were evaluated for a period of 48 h. The MICs and minimum bactericidal concentrations (MBCs) of free and liposomal formulations were determined with P. aeruginosa strains isolated from CF patients. Liposomal clarithromycin activity against biofilm-forming P. aeruginosa was compared to that of free antibiotic using the Calgary Biofilm Device (CBD). The effects of subinhibitory concentrations of free and liposomal clarithromycin on bacterial virulence factors and motility on agar were investigated on clinical isolates of P. aeruginosa. The cytotoxicities of the liposome preparations and free drug were evaluated on a pulmonary epithelial cell line (A549). The average diameter of the formulations was >222 nm, with encapsulation efficiencies ranging from 5.7% to 30.4%. The liposomes retained more than 70% of their drug content during the 48-h time period. The highly resistant strains of P. aeruginosa became susceptible to liposome-encapsulated clarithromycin (MIC, 256 mg/liter versus 8 mg/liter; P < 0.001). Liposomal clarithromycin reduced the bacterial growth within the biofilm by 3 to 4 log units (P < 0.001), significantly attenuated virulence factor production, and reduced bacterial twitching, swarming, and swimming motilities. The clarithromycin-entrapped liposomes were less cytotoxic than the free drug (P < 0.001). These data indicate that our novel formulations could be a useful strategy to enhance the efficacy of clarithromycin against resistant P. aeruginosa strains that commonly affect individuals with cystic fibrosis.

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confidence: 99%

“…The CFTR molecule is a 1,480-amino-acid membrane-bound chloride channel (7). The structure and function of the channel in CF are compromised by over 1,800 types of mutations (2). The most prevalent mutation, delta F 508, is a deletion of phenylalanine at position 508 and is responsible for 70% of CF cases worldwide (6,7).…”

mentioning

confidence: 99%

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Alhajlan

Alhariri

Omri

2013

Antimicrob Agents Chemother

116

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“…V456A is a missense mutation in exon 9 of CFTR which results in change of valine to an alanine in CRTR protein. Case 9 of present study and two other previously reported female cases from India and Pakistan who were homozygous for this mutation had intermediate sweat chloride concentrations with mild to moderate phenotype leading to delayed diagnosis of CF [36]. 1161delC mutation has been previously reported from Indian, Pakistani and Bahraini patients.…”

Section: Discussionmentioning

confidence: 52%

Phenotypic spectrum and genetic heterogeneity of cystic fibrosis in Sri Lanka

et al. 2019

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Background Cystic fibrosis has been largely under-diagnosed and thus, limited data is available on the incidence of cystic fibrosis in Sri Lanka. Our aim is to describe the phenotypic and genotypic spectrum of children with cystic fibrosis in Sri Lanka. Case presentation This report describes 10 unrelated cystic fibrosis cases with phenotypic features of cystic fibrosis and abnormal or intermediate sweat tests. The most common phenotypic features in this sample of symptomatic patients were persistent or recurrent lower respiratory tract infections, failure to thrive and Pseudo-Bartter syndrome. Altogether 7 cystic fibrosis causing mutations were identified in 10 patients. Except delta F508 which is the commonest mutation worldwide all the other mutations detected in Sri Lankan patients are rare mutations. 1161delC and V456A detected in our patients are South Asian mutations. The other mutations such as [C.1282C > G; C.2738A > G], C.53 + 1G > C, 2184insA and a deletion encompassing exons 4 to 11 have been reported previously from European patients with cystic fibrosis. Conclusion These cases highlight the importance of considering the diagnosis of cystic fibrosis in children and young adults presenting with persistent respiratory tract infections associated with severe malnutrition and Pseudo-Bartter syndrome, especially in low income countries where newborn screening for cystic fibrosis is not available. The spectrum of CFTR mutations in Sri Lanka is heterogeneous and possibly linked to genetic flow from Indian subcontinent and Europe. The common mutations should be identified by sequencing the entire CFTR gene in adequate number of cystic fibrosis patients in order to design a mutation panel for common regional mutations.

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“…Data suggest that more than 160 CFTR variants have been identified on approximately 3700 Asian CF chromosomes. Overall, F508del (p.Phe508del, c.1521_1523delCTT) remains the most common variant in Asian countries with few exceptions (Table ) . However, F508del constitutes only 12–31% of Asian CF alleles compared with 66% in the worldwide CF population comprised mainly from North America, Europe, Canada, Australia and New Zealand (http://www.genet.sickkids.on.ca/app).…”

Section: Distribution and Functional Consequences Of Cftr Variants Inmentioning

confidence: 99%

“…There are 116 additional rare CFTR variants reported from Asian countries and the majority of these variants have been observed only once. Among these variants 24 are from South Asia, 54 from Middle East Asia and 38 from East Asia (Table ) . The Delexon 16‐17b variant ( CFTR dele18‐20) has been observed in both Chinese and Japanese CF individuals .…”

Section: Distribution and Functional Consequences Of Cftr Variants Inmentioning

confidence: 99%

Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next‐generation treatments

et al. 2015

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Cystic fibrosis (CF) in the Asian population is less frequently reported due to under-diagnosis and lack of centralized CF patient registries. Clinical studies on CF cases from Asia have documented a severe course of the disease. The spectrum of the cystic fibrosis transmembrane conductance regulator (CFTR) variants in this population is quite heterogeneous. In total, 166 variants have been reported on approximately 3700 Asian CF chromosomes. The frequency of F508del among Asians is low compared with Caucasians. Recent in vitro studies have shown promise of small molecule correction and potentiation of 45 different CFTR variants. Of these variants, 16 (including G551D and F508del) have also been observed among Asian CF individuals. We suggest undertaking molecular studies extensively to annotate CFTR variants that will help Asian CF individuals to benefit from the precision medicine gaining momentum in the Western countries.

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Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians

Abstract: We provide evidence that V456A can cause significant pulmonary disease in South Asian Cystic Fibrosis patients.

Cited by 9 publications

References 14 publications

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Efficacy and Safety of Liposomal Clarithromycin and Its Effect on Pseudomonas aeruginosa Virulence Factors

Phenotypic spectrum and genetic heterogeneity of cystic fibrosis in Sri Lanka

Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next‐generation treatments

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