ABCMdb

PMID: 18178635

Stanke F, Ballmann M, Bronsveld I, Dork T, Gallati S, Laabs U, Derichs N, Ritzka M, Posselt HG, Harms HK, Griese M, Blau H, Mastella G, Bijman J, Veeze H, Tummler B
Diversity of the basic defect of homozygous CFTR mutation genotypes in humans.
J Med Genet. 2008 Jan;45(1):47-54., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCC7 p.Arg553* ABCC7 p.Gly314Glu ABCC7 p.Arg1162* ABCC7 p.Leu997Phe ABCC7 p.Glu92Lys ABCC7 p.Trp1098Leu Results: CFTR activity in sweat gland, upper airways and distal intestine was normal for homozygous carriers of G314E or L997F and in the range of F508del homozygotes for homozygous carriers of E92K, W1098L, R553X, R1162X, CFTRdele2(ins186) or CFTRdele2,3(21 kb). Login to comment 4 ABCC7 p.Met1101Lys Homozygotes for M1101K, 1898+3 A-G or 3849+10 kb C-T were not consistent CF or non-CF in the three bioassays. Login to comment 42 ABCC7 p.Arg553* The homozygotes for the large out-of-frame 21 kb deletion of exons 2 and 312 of the CFTR gene (Fig 1B) or the nonsense mutation R553X showed indeed full-blown CFTR loss-of-function phenotypes in the bioassays. Login to comment 43 ABCC7 p.Arg1162* The two R1162X homozygous patients, however, had some chloride secretory activity in their intestine that consisted of both DIDS-sensitive and DIDS-insensitive components (fig 1D, tables 4 and 5). Login to comment 56 ABCC7 p.Glu92Lys ABCC7 p.Trp1098Leu The homozygotes for E92K,16 W1098L or M1101K17 showed highly elevated sweat chloride concentrations in the CF range on several occasions, whereas the homozygotes for G314E18 or L997F19 20 had normal sweat electrolytes like non-CF healthy controls (table 2). Login to comment 58 ABCC7 p.Glu92Lys Only the E92K homozygote showed the CF pattern of a large response to amiloride and of a low chloride diffusion potential. Login to comment 59 ABCC7 p.Gly314Glu ABCC7 p.Met1101Lys ABCC7 p.Glu92Lys ABCC7 p.Glu92* The missense mutation E92K results from a G-to-A transition in the first base of exon 4 and hence may not also lead to the substitution of a glutamate by a lysine but also may affect splicing as it has been observed for the stop mutation E92X.21 The G314E and the M1101K homozygotes exhibited an intermediate chloride secretory phenotype between typical CF and typical non-CF. Login to comment 61 ABCC7 p.Gly314Glu ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Leu997Phe ABCC7 p.Glu92Lys ABCC7 p.Trp1098Leu The transport rates were in the upper CF range (E92K, W1098L, one M1101K sibling), in the intermediate range between CF and non-CF (the other two M1101K siblings) or in the normal range (L997F, G314E) (fig 1C). Login to comment 62 ABCC7 p.Gly314Glu ABCC7 p.Met1101Lys ABCC7 p.Leu997Phe The tissue specimens from two M1101K homozygous siblings expressed two patterns of chloride secretory responses that are consistent with the presence of both CFTR and the alternative chloride channel ORCC (fig 1E, table 5).7 Since the outcome of NPD, ICM, sweat test and clinical examination was normal in the G314E or L997F homozygotes, the diagnosis of CF that had been based on mutation reports in the literature,18 19 positive family anamnesis or suggestive respiratory symptoms, was withdrawn for these two individuals. Login to comment 68 ABCC7 p.Arg553* ABCC7 p.Arg553* Loss-of-function mutations such as CFTRdele2,3(21 kb) or R553X were not distinguishable in their clinical phenotypes from those of F508del homozygotes, although the consequences at the molecular level such as nonsense mediated decay and exon skipping22 or defective maturation and trafficking of protein1 are different. Login to comment 70 ABCC7 p.Arg553* ABCC7 p.Arg553* ABCC7 p.Gly314Glu ABCC7 p.Gly314Glu ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Arg1162* ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Met1101Lys ABCC7 p.Leu997Phe ABCC7 p.Leu997Phe ABCC7 p.Glu92Lys ABCC7 p.Glu92Lys ABCC7 p.Trp1098Leu ABCC7 p.Trp1098Leu Splice site mutations, for example, were associated with progressive lung disease and a Table 2 Assessment of basic defect (A): sweat tests and nasal potential difference (NPD) measurements (mV) Patient number CFTR genotype Sweat chloride concentration (mval/l) Basal PD (mV) Change in PD (mV) Day of assessment Prior tests (age) Amiloride Chloride-free + isoproterenol Out-of-frame deletion 1 CFTRdele2,3(21 kb)/CFTRdele2,3(21 kb) 103 95 (10 mo) 260 22 210 Nonsense mutation 2 R553X/R553X 96 100 (16 mo) 262 34 27 3 R1162X/R1162X 98 110 (2 y 1 mo) 248 23 24 4 R1162X/R1162X 104 112 (1 mo) 239 30 0 Splice-site mutation 5 1898+3 A-G/1898+3 A-G 73 69 (4 mo) 233 21 23 6 3849+10 kb C-T/3849+10 kb C-T 92 64 (20 y 5 mo) 244 30 212 49 (28 y 4 mo) 7 3849+10 kb C-T/3849+10 kb C-T 20 50 (11 y 2 mo) 227 12 +3 In-frame deletion 8 CFTRdele2(ins186)/CFTRdele2(ins186) 102 134 (4 mo) 245 30 21 9 CFTRdele2(ins186)/CFTRdele2(ins186) 100 119 (9 y) 248 31 28 10 CFTRdele2(ins186)/CFTRdele2(ins186) 131 100 (4 y) 258 41 212 Missense mutation 11 E92K/E92K 118 93 (8 mo) 252 20 211 12 G314E/G314E 15 43 (6 y 2 mo) 219 4 216 13 L997F/L997F 8 14 W1098L/W1098L 107 118 (2 mo) 15 M1101K/M1101K 108 120 256 33 216 16 M1101K/M1101K 130 120 264 26 215 17 M1101K/M1101K 118 229 13 210 F508del/F508del (n = 74)7 106¡22 256¡10 28¡9 28¡5 non-CF (n = 25) 16¡9 220¡10 11¡6 230¡8 Sibpairs: patients 3 & 4, 6 & 7, 9 & 10, 15, 16 & 17. Login to comment 78 ABCC7 p.Glu92Lys ABCC7 p.Asp110His E92K and D110H (data not shown) are located in the first ectoplasmic loop. Login to comment 81 ABCC7 p.Met1101Lys ABCC7 p.Trp1098Leu The mutations W1098L and M1101K reside in the cytoplasmic loop 4 (residues 1035-1102). Login to comment 82 ABCC7 p.Met1101Lys ABCC7 p.Trp1098Arg Heterologously expressed, recombinant mutants W1098R and M1101K were defective in CFTR maturation and non-functional in anion efflux assays.6 In contrast, the four homozygous patients unequivocally demonstrated substantial residual chloride conductance in the NPD and ICM bioassays (table 4). Login to comment 86 ABCC7 p.Gly314Glu ABCC7 p.Leu997Phe The non-conservative amino acid substitutions L997F and G314E did not impair chloride conductance in sweat glands, airways and intestine. Login to comment 89 ABCC7 p.Gly551Asp ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Gly314Glu ABCC7 p.Gly1249Glu Several well characterised severe mutations occur in the evolutionarily conserved Walker (G1244E, G1249E) or dodecapeptide motifs (G551D, G1349D) of the ABC transporter CFTR.1 The missense mutants G622D23 in the regulatory domain and G314E in the fifth transmembrane region led to no clinical symptoms of CF. Login to comment 97 ABCC7 p.Gly314Glu ABCC7 p.Arg1162* ABCC7 p.Met1101Lys ICM recordings of individuals homozygous for CFTRdele2,3(21 kb) (A), 1898+3 A-G (B), G314E (C), R1162X (D), M1101K (E) or of a healthy non-CF individual (F). Login to comment