ABCMdb

PMID: 22274833

Hentschel J, Riesener G, Nelle H, Stuhrmann M, Schoner A, Sommerburg O, Fritzsching E, Mall MA, von Eggeling F, Mainz JG
Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Disease-causing mutation or benign alteration?
Eur J Pediatr. 2012 Jul;171(7):1039-46. doi: 10.1007/s00431-012-1672-1. Epub 2012 Jan 25., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC7 p.Met348Lys ORIGINAL ARTICLE Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Login to comment 4 ABCC7 p.Arg347Pro Persisting respiratory symptoms and failure to thrive prompted cystic fibrosis diagnostics, which showed the lack of wild-type signal for the mutation R347P suggesting a homozygous deletion or an alteration different from the known mutation at this position. Login to comment 5 ABCC7 p.Met348Lys Sequencing of this region revealed the homozygous substitution 1175 T>A (HGVS: c.1043 T>A) in exon 7 resulting in the homozygous amino acid change M348K. Login to comment 7 ABCC7 p.Met348Lys Computational analysis tools classified M348K as 'presumably disease causing.` In our patient, sweat testing and electrophysiological assessment of CFTR function in native rectal epithelium demonstrated normal Cl- secretion. Login to comment 8 ABCC7 p.Met348Lys Conclusion: We assume that the homozygous alteration M348K is a harmless variant rather than a CF-causing mutation. Login to comment 11 ABCC7 p.Met348Lys M348K . Login to comment 16 ABCC7 p.Met348Lys We report on the first patient with homozygosity for the mutation M348K, with so far unknown clinical relevance. Login to comment 17 ABCC7 p.Met348Lys Until now, only three cases with heterozygote M348K mutation have been reported [3,5,6]. Login to comment 18 ABCC7 p.Met348Lys First detected in a severely affected patient carrying F508del on the other allele [3], M348K was classified as a disease-causing mutation. Login to comment 19 ABCC7 p.Met348Lys Likewise, M348K is listed as a 'disease-causing mutation` in the Human Genome Mutation Database [9] which is the basis for training of most of the prediction tools. Login to comment 22 ABCC7 p.Met348Lys ABCC7 p.Leu346Pro In another publication, M348K was found together with the mutation L346P in a 48-year-old unaffected individual [6]. Login to comment 23 ABCC7 p.Leu346Pro L346P in combination with F508del or 1677delTA (c.1545_1546delTA) leads to a mild or atypical phenotype. Login to comment 24 ABCC7 p.Met348Lys ABCC7 p.Met348Lys ABCC7 p.Leu346Pro Therefore, the authors suggest that either L346P is dominant over M348K or that M348K is a J. Hentschel (*) :G. Riesener :H. Nelle :F. von Eggeling Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07743 Jena, Germany e-mail: julia.hentschel@mti.uni-jena.de J. Hentschel :J. Login to comment 27 ABCC7 p.Gly1244Glu ABCC7 p.Asn1303Lys Previously, a clinically affected individual was described carrying G1244E and N1303K [5]. Login to comment 28 ABCC7 p.Gly1244Glu ABCC7 p.Met348Lys The healthy father was found to be compound heterozygous for M348K and G1244E. Login to comment 30 ABCC7 p.Met348Lys Taken together, the clinical relevance of the M348K mutation remains unclear. Login to comment 62 ABCC7 p.Arg334Trp ABCC7 p.Arg334Trp ABCC7 p.Met348Lys ABCC7 p.Met348Lys ABCC7 p.Arg764* ABCC7 p.Arg764* PMut predictions are based on the use of neural networks, and the tool is trained using a Fig. 1 Original recordings of the effects of cAMP-dependent activation (IBMX/forskolin) and cholinergic activation (carbachol) on Vte and Rte in rectal tissues from a the patient (M348K/M348K) showing normal Cl- secretory responses (lumen-negative Vte responses), b a CF patient (1717- 1G→;A/R764X) with no detectable Cl- secretion (lumen-positive Vte responses) and c a CF patient (F508del/R334W) expressing residual Cl- secretion, as evidenced by the attenuated lumen-negative Vte response and biphasic response to carbachol. Login to comment 64 ABCC7 p.Arg347Pro ABCC7 p.Arg347Pro Rte was determined from Vte deflections obtained by pulsed current injection Blank mutationcontrol patient Fig. 2 Results of the INNO LiPA CFTR17+Tn update analysis, which showed the lack of wild-type signal for the mutation R347P suggesting a homozygous deletion or an alteration different from the known mutation at this position Table 1 Result of STR analysis STR-Marker Chromosomal localizationa Allele distribution Allele distribution Allele distribution Interpretation Mother Father Child D7S3051 7p14 a-c b-c a-b Informative normal D7S2559 7p21.1 b-b a-b a-b Non-informative D7S817 7p14.3 a-c b-d c-d Informative normal D7S2846 7p14.1 a-c b-d a-d Informative normal D7S1830 7p12.1 a-c b-b a-b Informative normal D7S3046 7q11.22 b-d a-c a-b Informative normal D7S2204 7q21.11 a-a b-c a-b Informative normal D7S820 7q21.11 a-d b-c b-d Informative normal D7S1799 7q21.1 b-c a-c c-c Non-informative D7S821 7q21.3 a-b a-b b-b Non-informative D7S1804 7q32.2 b-c a-b b-b Non-informative D7S1824 7q34 a-a b-c a-c Informative normal D7S2461 7q36.1 b-c a-b b-b Non-informative D7S3058 7q36.2 a-c b-b b-c Informative normal a Chromosomal localisation according to www.genome.ucsc.edu [24] M F C M F C M F C M F C M F C GATA137H02 D7S3058D7S1824D7S2846D7S817 D7S820 (7q21.11) D7S1799 (7q21.1) D7S1804 (7q32.2) Mother Father Child D7S2461 (7q36.1) a b Fig. 3 a Uniparental disomy 7 (UPD 7) analysis. Login to comment 72 ABCC7 p.Met348Lys ABCC7 p.Met348Lys The patient`s sample revealed a homozygous change T>A at the position 1175 (c.1043T>A) which results in amino acid replacement from methionine to lysine at codon 348 (M348K). Login to comment 74 ABCC7 p.Met348Lys M348K was not found in healthy controls and carbachol-induced Cl- secretion (Fig. 1b), whereas tissues from CF patients carrying at least one mutation with residual Cl- channel function (CFresidual) show attenuated cAMP-mediated Cl- secretory responses (previously published mean of CFresidual tissues: ΔIsc0-28.1±2.9 μA/cm2 [8]) followed by biphasic responses to carbachol (Fig. 1c). Login to comment 77 ABCC7 p.Arg347Pro However, the wild-type signal for R347P was lost (Fig. 2). Login to comment 84 ABCC7 p.Met348Lys Codon 348 (ATG) was changed to AAG resulting in an amino acid change from methionine to lysine (M348K). Login to comment 85 ABCC7 p.Met348Lys Sequencing of parents and healthy elder brothers of the index patient revealed heterozygosity for M348K for all tested family members (Fig. 4). Login to comment 86 ABCC7 p.Met348Lys If one of the healthy brothers also had a homozygous M348K substitution, the alteration could have been easily classified as benign. Login to comment 87 ABCC7 p.Met348Lys M348K was not found in four sequenced control samples. Login to comment 90 ABCC7 p.Met348Lys Using the prediction tool PolyPhen2 [16], M348K was found to be 'probably damaging` (score 0.997). Login to comment 91 ABCC7 p.Met348Lys Also PMut [15] assessed the alteration M348K as 'pathological` with a score of 0.8245 (threshold for pathological alterations>0.5) and a confidence level of the prediction of 6 (00low, 90high confidence). Login to comment 96 ABCC7 p.Met348Lys ABCC7 p.Met348Lys 3D structure of the CFTR protein illustrating the location of M6 (which harbours the M348K) within the MSD1 which forms the pore of the CFTR channel together with MSD2 further mutations and deletions, all 27 exons and flanking intronic regions of the CFTR gene were sequenced, and a MLPA analysis was performed, which revealed no further mutation in addition to the initially found M348K. Login to comment 97 ABCC7 p.Met348Lys Discussion This is the first report of a patient with a homozygous M348K CFTR mutation. Login to comment 101 ABCC7 p.Met348Lys Interestingly, this is inconsistent with previously evaluated prediction tools which classified the alteration M348K as 'presumably disease causing` or 'probably damaging`. Login to comment 106 ABCC7 p.Met348Lys Half of the detected mutations are associated with CF phenotype; for seven alterations (including M348K), the phenotype is not clear and investigations within the CFTR2 project are ongoing. Login to comment 110 ABCC7 p.Arg347Pro These properties can influence the conductance of the CFTR protein as it is published for mutation R347P [21]. Login to comment 112 ABCC7 p.Met348Lys Besides, tools were trained with published disease mutations and M348K mutation is listed as one. Login to comment 113 ABCC7 p.Met348Lys Taken together, our investigation suggests that the CFTR alteration M348K is a harmless variant rather than a CF-causing mutation. However, the question cannot finally be answered, whether the ongoing clinical problems like bronchial hyper reactivity and airway colonization with pathogens like MR S. aureus, H. influenzae and A. lwoffii are related to the changes in the CFTR gene or if they are due to premature birth. Login to comment 121 ABCC7 p.Met348Lys It could be speculated that a M348K mutation causes a decrease in CFTR function, but at the same time, a positive influence of modifiers results in residual function which can be measured via electrophysiology. Login to comment