3849 + 10 kb C → T Splicing Mutation in Hispanic CF Patients

Liang, Min-Hui; Wertz, Karin; Bowman, C. Michael; Hsu, Evelyn; Shapiro, Bertrand J.; Wong, Lee‐Jun C.

doi:10.1006/mgme.1998.2710

Cited by 10 publications

(6 citation statements)

References 12 publications

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“…Recent studies [Mercier et al, , 1994 show that R1162X has been found in certain Native American populations, as well as the U.S. Hispanic CF patient pool. 3849+10KbC→T has been found in both the Mexican [Villalobos-Torres et al, 1997;Liang et al, 1998;Orozco et al, 2000] and the Southwest U.S. Hispanic , as well as certain Native American CF patients [Mercier et al, 1994], but is not a common mutation in Europe (Table 1). Those regions of Europe that have also been shown to exhibit this mutation (i.e., Poland and Ashkenazi Jewish populations) do so most likely as a result of mutational recurrence , and not a direct founder effect.…”

Section: Speculation and Future Issuesmentioning

confidence: 99%

Cystic fibrosis: A worldwide analysis ofCFTR mutations?correlation with incidence data and application to screening

et al. 2002

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Although there have been numerous reports from around the world of mutations in the gene of chromosome 7 known as CFTR (cystic fibrosis transmembrane conductance regulator), little attention has been given to integrating these mutant alleles into a global understanding of the population molecular genetics associated with cystic fibrosis (CF). We determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort designed to: 1) increase our understanding of ancestrygenotype relationships, 2) compare mutational arrays with disease incidence, and 3) gain insight for decisions regarding screening program enhancement through CFTR multi-mutational analyses. Information on all mutations that have been published since the identification and cloning of the CFTR genes most common allele, DF508 (or F508del), was reviewed and integrated into a centralized database. The data were then sorted and regional CFTR arrays were determined using mutations that appeared in a given region with a frequency of 0.5% or greater. Final analyses were based on 72,431 CF chromosomes, using data compiled from over 100 original papers, and over 80 regions from around the world, including all nations where CF has been studied using analytical molecular genetics. Initial results confirmed wide mutational heterogeneity throughout the world; however, characterization of the most common mutations across most populations was possible. We also examined CF incidence, DF508 frequency, and regional mutational heterogeneity in a subset of populations. Data for these analyses were filtered for reliability and methodological strength before being incorporated into the final analysis. Statistical assessment of these variables revealed that there is a significant positive correlation between DF508 frequency and the CF incidence levels of regional populations. Regional analyses were also performed to search for trends in the distribution of CFTR mutations across migrant and related populations; this led to clarification of ancestrygenotype patterns that can be used to design CFTR multi-mutation panels for CF screening programs. From comprehensive assessment of these data, we offer recommendations that multiple CFTR alleles should eventually be included to increase the sensitivity of newborn screening programs employing two-tier testing with trypsinogen and DNA analysis. Hum Mutat 19:575606, 2002.

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Section: Speculation and Future Issuesmentioning

confidence: 99%

Cystic fibrosis: A worldwide analysis ofCFTR mutations?correlation with incidence data and application to screening

et al. 2002

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“…In Europe, its frequency is 0.15% of CF chromosomes, although it is more common among Jews from eastern Europe and in the Polish population (,4% of CF alleles) [17][18][19][20]. A higher frequency (,2%) is also reported in Hispanic and Native American patients [21,22]. The 3849+10kbC-.T mutation was found to be associated with four microsatellite haplotypes in Europe, while a fifth haplotype was identified in the Native American population, consistent with the hypothesis of a recurrent mutation [22,23].…”

Section: Mild Phenotype Associated With Two Cftr Mutations I Duguépémentioning

confidence: 99%

The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype

Duguépéroux

Braekeleer²

2005

Eur Respir J

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Most cystic fibrosis (CF) transmembrane receptor mutations are rare. The French CF Registry offers an opportunity to study the genotype-phenotype relationship of these rare alleles.Since 1992, 39 CF patients carrying one copy of the 3849+10kbC-.T mutation and 88 the 2789+5G-.A allele have been seen at least once in a CF care centre. Among them, 16 carrying the 3849+10kbC-.T/DF508 genotype and 34 with the 2789+5G-.A/DF508 genotype were seen in 2000. Their age at diagnosis, sweat chloride concentration, anthropometric and lung function results, and clinical aspects were compared with those homozygous for the DF508 mutation matched for sex, age and CF care centre.Major differences, most of them statistically significant, in the age at diagnosis, prevalence of pancreatic insufficiency, and other clinical signs, anthropometric and lung function measures were observed between both compound heterozygote groups and their matched DF508/DF508 groups. The mean sweat chloride concentration was also lower (close to normal values) among 3849+10kbC-.T/DF508 patients, but not among 2789+5G-.A/DF508 patients.In conclusion, both mutations studied here are associated with a milder course of cystic fibrosis disease. The 3849+10kbC-.T and 2789+5G-.A alleles are splice site mutations, leading to abnormal mRNA; however, a small amount of normally spliced transcripts can also be detected. The presence of these small amounts of normal cystic fibrosis transmembrane receptor protein in these cystic fibrosis patients is likely to be responsible for the milder severity of disease and a better life expectancy.

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“…This mutation causes an alternative splice site which results in either a low level of normal functional protein or partially functional protein [28]. This mutation was found to occur at a significantly higher frequency in the Hispanic CF population than in the general CF population [24]. The detection of mutations that escape TTGE detection may be improved by optimizing TTGE conditions, such as changing the temperature range, ramp rate, and percentage of gel.…”

Section: Discussionmentioning

confidence: 97%

“…These mutations produce truncated CFTR pro- teins that are lacking important functional domains, and thus, are predicted to be deleterious. It is interesting to note that the patients harboring these deleterious mutations had severe clinical course including pancreatic insufficiency, impaired pulmonary function, and repetitive microbial infections in the respiratory tract [11,12,16,20,21,[24][25][26]. These data suggested that the majority of the unidentified mutations were severe mutations, further underscoring the importance of whole gene mutation analysis for appropriate genetic counseling and patient care.…”

Section: Identification Of Novel and Rare Cftr Mutationsmentioning

confidence: 94%

Detection of CFTR mutations using temporal temperature gradient gel electrophoresis

Wong

Alper

2004

Electrophoresis

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Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is one of the most common autosomal recessive diseases with variable incidences and mutation spectra among different ethnic groups. Current commercially available mutation panels designed for the analysis of known recurrent mutations have a detection rate between 38 to 95%, depending upon the ethnic background of the patient. We describe the application of a novel mutation detection method, temporal temperature gradient gel electrophoresis (TTGE), to the study of the molecular genetics of Hispanic CF patients. TTGE effectively identified numerous rare and novel mutations and polymorphisms. One interesting observation is that the majority of the novel mutations are splice site, frame shift, or nonsense mutations that cause severe clinical phenotypes. Our data demonstrate that screening of the 27 exons and intron/exon junctions of the CFTR gene by TTGE greatly improves the molecular diagnosis of Hispanic CF patients.

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3849 + 10 kb C → T Splicing Mutation in Hispanic CF Patients

Cited by 10 publications

References 12 publications

Cystic fibrosis: A worldwide analysis ofCFTR mutations?correlation with incidence data and application to screening

Cystic fibrosis: A worldwide analysis ofCFTR mutations?correlation with incidence data and application to screening

The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype

Detection of CFTR mutations using temporal temperature gradient gel electrophoresis

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