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Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia.

ABSTRACT: BACKGROUND:Cystic fibrosis (CF) occurs in populations in Saudi Arabia and the Gulf area. Approximately 2000 known variants have been identified for the CF transmembrane conductance regulator (CTFR) gene. Screening for ten of the most common variants can detect 80% of alleles. OBJECTIVE:Determine the pattern of CFTR variants in the CF population of Saudi Arabia. DESIGN:A retrospective, descriptive. SETTING:Tertiary care center. PATIENTS AND METHODS:We examined the medical records of 396 confirmed CF patients of all age groups that were positive for a CFTR variant from the period of 1 January 1998 to 1 December 2017. MAIN OUTCOME MEASURES:Zygosity, morbidity and mortality patterns of different types of CFTR variants. SAMPLE SIZE:312 families that included 396 patients. RESULTS:Of 48 variants identified, 6 were novel, having not been described in the medical literature. A homozygous state was found in 283 families (90.7%) and compound heterozygosity in 23 (7.4%). Six families were heterozygous (1.9%). Median age (interquartile range) was 10.2 months (4.4 months to 5.7 years) at diagnosis and 9.7 (5.4-16.5) years at follow up. Of 396 patients, 378 patients (95.5%) survived and 18 (4.5%) died. The ten most common variants identified in descending frequency were: p.Gly473GlufsX54 in 98 alleles (16%), p.Ile1234Val in 66 alleles (11%), F508del in 64 alleles (11%), 711+1G>T in 62 alleles (10%), 3120+1G>A in 62 alleles (11%), p.His139Leuin 38 alleles (6.4%), p.Gln637Hisfs in 30 alleles (5.2%), p.Ser549Arg in 27 alleles (4.5%), p.Asn1303Lys in 14 alleles (2.3%), delExon19-21in 10 alleles (1.6%). This analysis identified 79.2% of our CFTR variants. CONCLUSION:CFTR mutational patterns in our CF population are characterized by a high allelic heterogeneity. The high prevalence of homozygous variants reflects the high level of consanguinity between parents. LIMITATIONS:Our CFTR screening reflected only about 80% of CF patients in Saudi Arabia. CONFLICT OF INTEREST:None.

SUBMITTER: Banjar HH

PROVIDER: S-EPMC7012030 | biostudies-literature | 2020 Jan-Feb

REPOSITORIES: biostudies-literature

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Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia.

Banjar Hanaa Hasan HH Tuleimat Lin L El Seoudi Abdul Aziz Agha AAA Mogarri Ibrahim I Alhaider Sami S Nizami Imran Yaqoob IY AlMaghamsi Talal T Alkaf Sara Andulrahman SA Moghrabi Nabil N

Annals of Saudi medicine 20200101 1

<h4>Background</h4>Cystic fibrosis (CF) occurs in populations in Saudi Arabia and the Gulf area. Approximately 2000 known variants have been identified for the CF transmembrane conductance regulator (CTFR) gene. Screening for ten of the most common variants can detect 80% of alleles.<h4>Objective</h4>Determine the pattern of CFTR variants in the CF population of Saudi Arabia.<h4>Design</h4>A retrospective, descriptive.<h4>Setting</h4>Tertiary care center.<h4>Patients and methods</h4>We examined ...[more]

PMID: 32026723

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Project description:Background: Most cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that lead to protein misfolding and degradation by the ubiquitin-proteasome system. Previous studies demonstrated that PIAS4 facilitates the modification of wild-type (WT) and F508del CFTR by small ubiquitin-like modifier (SUMO)-1, enhancing CFTR biogenesis by slowing immature CFTR degradation and producing increased immature CFTR band B. Methods: We evaluated two correction strategies using misfolding mutants, including the common variant, F508del. We examined the effects on mutant expression of co-expression with PIAS4 (E3 SUMO ligase), and/or the corrector, C18. To study the impact of these correction conditions, we transfected CFBE410- cells, a bronchial epithelial cell line, with a CFTR mutant plus: (1) empty vector, (2) empty vector plus overnight 5 μM C18, (3) PIAS4, and (4) PIAS4 plus C18. We assessed expression at steady state by immunoblot of CFTR band B, and if present, band C, and the corresponding C:B band ratio. The large PIAS4-induced increase in band B expression allowed us to ask whether C18 could act on the now abundant immature protein to enhance correction above the control level, as reported by the C:B ratio. Results: The data fell into three mutant CFTR categories as follows: (1) intransigent: no observable band C under any condition (i.e., C:B = 0); (2) throughput responsive: a C:B ratio less than control, but suggesting that the increased band C resulted from PIAS4-induced increases in band B production; and (3) folding responsive: a C:B ratio greater than control, reflecting C18-induced folding greater than that expected from increased throughput due to the PIAS4-induced band B level. Conclusion: These results suggest that the immature forms of CFTR folding intermediates occupy different loci within the energetic/kinetic folding landscape of CFTR. The evaluation of their properties could assist in the development of correctors that can target the more difficult-to-fold mutant conformations that occupy different sites within the CFTR folding pathway.

Dataset Information

Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia.

Publications

Genotype patterns for mutations of the cystic fibrosis transmembrane conductance regulator gene: a retrospective descriptive study from Saudi Arabia.

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