ABCMdb

PMID: 19181743

Sharma N, Acharya N, Singh SK, Singh M, Sharma U, Prasad R
Heterogenous spectrum of CFTR gene mutations in Indian patients with congenital absence of vas deferens.
Hum Reprod. 2009 May;24(5):1229-36. Epub 2009 Jan 30., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCC7 p.Leu69His ABCC7 p.Gly126Ser ABCC7 p.Phe157Cys ABCC7 p.Phe87Ile ABCC7 p.Tyr852Phe ABCC7 p.Glu543Ala ABCC7 p.Asp1270Glu Novel CFTR mutations identified were L69H, F87I, G126S, F157C, E543A, Y852F and D1270E. Login to comment 55 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Asn1303Lys ABCC7 p.Gly542* We next screened R117H, N1303K and R553X each by single ARMS PCR and 621 þ 1G-T, G542X, G551D and W1282X by multiplex ARMS PCR. Login to comment 56 ABCC7 p.Ala455Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro CFTR mutations investigated by restriction analysis of PCR products were R334W (MspI), R347P (NcoI), A455E (AciI), 2789 þ 5 . Login to comment 57 ABCC7 p.Arg1162* G-A (SspI), R1162X (DdeI) and 3849 þ 10 kb . Login to comment 73 ABCC7 p.Arg117His In the CAVD patients with normal renal development, the initial screening identified one extra, R117H mutation in three chromosomes. Login to comment 74 ABCC7 p.Leu69His ABCC7 p.Gly126Ser ABCC7 p.Phe157Cys ABCC7 p.Phe87Ile ABCC7 p.Tyr852Phe ABCC7 p.Glu543Ala ABCC7 p.Asp1270Glu SSCP analysis performed in patients with only one or no mutation revealed nine further mutations on one allele each including seven new sequence alterations: L69H, F87I, G126S, F157C, E543A, Y852F and D1270E (Table I). Login to comment 75 ABCC7 p.Arg117His Other identified mutations R117H, 3120 þ 1 . Login to comment 76 ABCC7 p.Pro1021Ser G-A and P1021S have been described previously in studies of patients with CAVD. Login to comment 78 ABCC7 p.Leu69His ABCC7 p.Glu543Ala ABCC7 p.Asp1270Glu Pathological predictions and multiple sequence alignments of novel substitution mutations The output prediction scores (http://blocks.fhrc.org/sift/SIFT.html) for L69H, E543A and D1270E were less than the 0.05 (threshold for pathological mutations) (Table II). Login to comment 79 ABCC7 p.Leu69His ABCC7 p.Gly126Ser ABCC7 p.Phe157Cys ABCC7 p.Phe87Ile ABCC7 p.Tyr852Phe ABCC7 p.Asp1270Glu Pathological predictions confirmed by another computer algorithm (http://genetics.bwh.harvard.edu/pph) revealed L69H, E543 and D1270E as deleterious mutations and other four mutations, F87I, G126S, F157C and Y852F, as benign sequence alterations (Table II). Login to comment 83 ABCC7 p.Phe87Ile genome.jp/) confirmed that the wild-type form of all the novel sequence variants, except F87I, was conserved across human, rhesus monkey, bovine, sheep, horse, dog, pig, rabbit and mouse (Fig. Login to comment 104 ABCC7 p.Gly126Ser None of the patients showed pulmonary or gastrointestinal symptoms of CF, but repeated respiratory infections or bronchitis and raised sweat chloride were documented in a CBAVD patient with F508del/G126S genotype. Login to comment 105 ABCC7 p.Arg117His ABCC7 p.Phe87Ile A compound heterozygous, R117H/F87I, genotype was identified in a CBAVD subject with normal sweat chloride and no CF-like symptoms. Login to comment 107 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Pro1021Ser ABCC7 p.Pro1021Ser ABCC7 p.Leu69His ABCC7 p.Gly126Ser ABCC7 p.Tyr852Phe ABCC7 p.Glu543Ala ABCC7 p.Asp1270Glu of alleles T5 Reduction of oligo T tract to 5T at 1342-6 Aberrant splicing Intron 8 25 F508del Deletion of 3 bp (CTT or TTT) between 1652 and 1655 Deletion of phenylalanine at 508 Exon 10 11 L69Ha T to A at 338 Leucine to histidine at 69 Exon 3 1 F87Ia T to A at 391 Phenylalanine to isoleucine Exon 3 1 R117H G to A at 482 Arginine to histidine at 117 Exon 4 3 G126Sa G to A at 508 Glycine to serine at 126 Exon 4 1 F157Ca T to G at 602 Phenylalanine to cystine at 157 Exon 4 1 E543Aa A to C at 1760 Glutamate to alanine at 543 Exon 11 1 Y852Fa A to T at 2687 Tyrosine to phenylalanine at 852 Exon 14a 1 3120 þ 1 G-A G to A 3120 þ 1 Aberrant splicing Intron 16 1 P1021S C to T at 3193 Proline to serine at 1021 Exon 17a 1 D1270Ea T to A at 3942 Aspartate to glutamate at 1270 Exon 20 1 Total chromosomes: 100; known mutations: 48%; unknown mutations: 52%. Login to comment 121 ABCC7 p.Leu69His ABCC7 p.Gly126Ser ABCC7 p.Phe157Cys ABCC7 p.Phe87Ile ABCC7 p.Tyr852Phe ABCC7 p.Glu543Ala ABCC7 p.Asp1270Glu Intriguingly, among the seven novel substitution mutations identified, L69H, E543A and D1270E were predicted to be damaging, whereas F87I, G126S, F157C and Y852F were possibly neutral (http://blocks.fhcrc.org/sift/SIFT.html and http://genetics.bwh. Login to comment 123 ABCC7 p.Leu69His It is noteworthy that L69H has been previously identified on one allele of the Indian classic CF patient (Sharma et al., 2009). Login to comment 128 ABCC7 p.Phe87Ile Since F87I mutation is not conserved across various species (http://align.genome.jp/), it implies that it is a rare neutral sequence variation rather than a disease-causing mutation. Login to comment 129 ABCC7 p.Gly126Ser ABCC7 p.Phe157Cys ABCC7 p.Tyr852Phe Other novel mutations (G126S, F157C and Y852F) have been identified as possibly neutral, but are aligned across different species. Login to comment 132 ABCC7 p.Leu69His ABCC7 p.Gly126Ser ABCC7 p.Phe157Cys ABCC7 p.Phe87Ile ABCC7 p.Glu543Ala ABCC7 p.Asp1270Glu ABCC7 p.Tyr852Ala In CBAVD patients, a high frequency of compound heterozygosity with severe/mild or mild/mild mutations has been reported Figure 1 Multiple alignments of CFTR amino acid sequences from different species (human, rhesus monkey, bovine, sheep, pig and mouse) and seven novel substitution mutations (L69H, F87I, G126S, F157C, E543A, Y852A and D1270E) identified in Indian CAVD patients. Login to comment 145 ABCC7 p.Arg117His ABCC7 p.Arg117His ABCC7 p.Gly126Ser ABCC7 p.Phe87Ile ABCC7 p.Tyr852Phe ABCC7 p.Asp1270Glu of patients (%) Two mutations detected 22% IVS8-T5/IVS8-T5 5 (10) (TG)12T5/(TG)12T5 2/2 2/2 1/1 1/1, 1/2 2 (4) (TG)12T5/(TG)13T5 1/1 2/1 2/1 (1), 2/2 (1) 1/1 (1), 1/2 (1) 2 (4) (TG)11T5/(TG12)T5 1/2 1/1 2/2 2/2 1 (2) IVS8-T5/F508del (TG)13T5/(TG10)T9 2/2 1/1 1/1 1/1 1 (2) IVS8-T5/R117H (TG)12T5/(TG)12T7 1/1 2/2 2/2 1/1 1 (2) IVS8-T5/Y852F (TG)12T5/(TG)12T7 1/1 1/2 2/1' 1/2 1 (2) IVS8-T5/D1270E (TG)12T5/(TG)12T9 1/1 1/1 2/2 2/2 1 (2) F508del/G126S (TG)10T7/(TG)11T7 2/2 1/1 1/1 1/1 1 (2) R117H/F87I (TG)12T7/(TG)12T7 1/1 2/1 2/2 1/2 1 (2) One mutation detected 52% F508del/? Login to comment 146 ABCC7 p.Leu69His 9 (18) (TG)10T9/(TG)12T7 2/2 1/1 1/1 1/1 (3), 1/2 (1) 4 (8) 2/2 1/1 1/1 2/2 1 (2) 2/2(1), 2/1(1) 1/1 1/1 1/1 (1), 1/2 (1) 2 (4) (TG)10T7/(TG11)T9 2/2 1/1 1/1 2/2 1 (2) (TG)10T9/(TG)13T7 2/2 1/2 1/1 2/2 1 (2) L69H/? Login to comment 147 ABCC7 p.Phe157Cys (TG)11T7/(TG13)T9 1/1 1/2 1 2 1 (2) F157C/? Login to comment 148 ABCC7 p.Glu543Ala (TG)11T7/(TG)11T9 1/1 1 2 2 1 (2) E543A/? Login to comment 149 ABCC7 p.Arg117His (TG)12T7/(TG)12T7 1/1 2 1 2 1 (2) R117H/? Login to comment