ABCMdb

PMID: 23361109

Sorio C, Angiari C, Johansson J, Verze G, Ettorre M, Buffelli M, Castellani C, Assael BM, Melotti P
Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation.
J Cyst Fibros. 2013 Dec;12(6):821-5. doi: 10.1016/j.jcf.2012.12.014. Epub 2013 Jan 27., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Ser977Phe ABCC7 p.Ser977Phe Case Study Impaired CFTR function in mild cystic fibrosis associated with the S977F/ T5TG12complex allele in trans with F508del mutation Claudio Sorio a , Chiara Angiari b , Jan Johansson a , Genny Verz&#e8; a, b , Michele Ettorre c , Mario Buffelli c , Carlo Castellani b , Baroukh Maurice Assael b , Paola Melotti b,Ìe; a Department of Pathology and Diagnostics, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy b Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata di Verona, Piazzale Aristide Stefani 1, 37126 Verona, Italy c Department of Neurological, Neuropsychological, Morphological and Motor Sciences, Section of Physiology, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy Received 8 November 2012; received in revised form 26 December 2012; accepted 29 December 2012 Available online 27 January 2013 Abstract Background: The S977F mutation (c.2930CNT) in the CFTR gene (CFTR/ABCC7) is extremely rare. Login to comment 1 ABCC7 p.Ser977Phe We describe the case of an adult patient carrying the complex allele S977F/T5TG12 in trans with the F508del mutation. Login to comment 34 ABCC7 p.Ser977Phe Following the detection of the F508del mutation, D-HPLC and sequencing were performed and results showed the presence of the IVS8-(TG)mTn polymorphic alleles (TG)12T5/(TG)10T9, and of the S977F mutation. Login to comment 35 ABCC7 p.Ser977Phe It was not possible to test the parents since they live in another region but three sisters were genotyped: one had S977F, IVS8-Tn: T5/T7; one no mutations/variants, IVS8-Tn: T7/T7; the other had F508del, IVS8-Tn: T9/T7. Login to comment 36 ABCC7 p.Ser977Phe From this we concluded that S977F was in cis with the polymorphic allele T5. In the transmembrane domain 9 the residue 977F is highly conserved among five species [6]. Login to comment 37 ABCC7 p.Ser977Phe In comparison with L977F, which is more conservative and considered as a polymorphism [6,7] or associated with increased susceptibility to pancreatic ductular obstruction, the rare mutation S977F [8] is less conservative. Login to comment 39 ABCC7 p.Gly542* ABCC7 p.Ser977Phe ABCC7 p.Ser977Phe This prediction is consistent with the case reported in the literature, where a subject carrying the S977F mutation, in addition to a "severe" classic CF-causing mutation on the other allele (CFTR genotype G542X/S977F), presented with clinical evidence of CF [9]. Login to comment 40 ABCC7 p.Leu997Phe This observation could well be applicable to L997F too. Login to comment 41 ABCC7 p.Arg117Leu L977F has been associated with CF and a complex allele (R117L,L977F) has recently been described that could account for the variable phenotype [10]. Login to comment 42 ABCC7 p.Arg117Leu The presence of R117L was excluded in our patient. Login to comment 43 ABCC7 p.Ser977Phe The case we describe, the S977F allele in cis with the polymorphic site TG12T5, allows the possibility that decreased mRNA expression, associated with the TG12T5 allele, participates together with the amino acid replacement, to CFTR functional impairment. Login to comment 45 ABCC7 p.Ser977Phe In the Clinical and Functional Translation of CFTR 2 (CFTR2) worldwide CF database, S977F is reported in 9 patients with 6 of them having F508del in trans. Login to comment 59 ABCC7 p.Ser977Phe It is worth underlining the fact that this report does not demonstrate the ability of the S977F mutation to cause a CF phenotype on its own but rather can be considered a mutation of varying clinical consequence: subjects need to be homozygous for this mutation in the absence of the T5TG12 genotype to properly assess the disease-causing potential of this mutation. Login to comment 60 ABCC7 p.Arg117His Furthermore, where genetic variants arise, the complete scanning of the gene is required since synergies in different variants/polymorphisms can affect the CFTR function and lead to manifestation of the disease, as in the case of R117H [16]. Login to comment