ABCMdb

ABCC7 p.His139Gln

ClinVar:	c.416A>G , p.His139Arg ? , not provided c.416A>T , p.His139Leu ? , not provided
CF databases:	c.416A>G , p.His139Arg (CFTR1) ? , A novel mutation was identified by DGGE and direct sequencing in a CF patient of Italian patient. The nucleotide change is A->G at position 548 in exon 4 leading to H139R c.416A>T , p.His139Leu (CFTR1) ? , This mutation has been identified in exon 4 as H139L (A to T at 548) in six Bahraini patients that belong to five unrelated families. The first patient is a heterozygous H139L / K1177X. The second and third patients are heterozygous siblings for 3120+1G->A. Finally the last three unrelated patients are heterozygous H139L / Unknown.
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), I: D (95%), K: D (95%), L: D (91%), M: D (95%), N: D (95%), P: D (95%), Q: D (85%), R: N (57%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] A novel ER J-protein DNAJB12 accelerates ER-associ... Cell Struct Funct. 2010;35(2):107-16. Epub 2010 Dec 8. Yamamoto YH, Kimura T, Momohara S, Takeuchi M, Tani T, Kimata Y, Kadokura H, Kohno K
A novel ER J-protein DNAJB12 accelerates ER-associated degradation of membrane proteins including CFTR.
Cell Struct Funct. 2010;35(2):107-16. Epub 2010 Dec 8., [PMID:21150129]

Abstract [show]
Cytosolic Hsc70/Hsp70 are known to contribute to the endoplasmic reticulum (ER)-associated degradation of membrane proteins. However, at least in mammalian cells, its partner ER-localized J-protein for this cellular event has not been identified. Here we propose that this missing protein is DNAJB12. Protease protection assay and immunofluorescence study revealed that DNAJB12 is an ER-localized single membrane-spanning protein carrying a J-domain facing the cytosol. Using co-immunoprecipitation assay, we found that DNAJB12 is able to bind Hsc70 and thus can recruit Hsc70 to the ER membrane. Remarkably, cellular overexpression of DNAJB12 accelerated the degradation of misfolded membrane proteins including cystic fibrosis transmembrane conductance regulator (CFTR), but not a misfolded luminal protein. The DNAJB12-dependent degradation of CFTR was compromised by a proteasome inhibitor, lactacystin, suggesting that this process requires the ubiquitin-proteasome system. Conversely, knockdown of DNAJB12 expression attenuated the degradation of CFTR. Thus, DNAJB12 is a novel mammalian ER-localized J-protein that plays a vital role in the quality control of membrane proteins.

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86 Since the highly conserved HPD motif in J-domains is generally required for their interaction with the partner Hsp70 family chaperones (Kampinga and Craig, 2010), we constructed a DNAJB12 mutant carrying a substitution mutation that alters this HPD motif to QPD (H139Q). Login to comment
87 When the H139Q mutant version of DNAJB12- Flag was expressed in HeLa cells, its expression level was almost comparable to that of wild-type DNAJB12-Flag (compare lane 3 with lane 2 in the bottom panel). Login to comment
106 On the other hand, the coexpression of the H139Q mutant version of DNAJB12-Flag gave a more modest effect, as only the level of the C form was decreased significantly (lane 3) (see Discussion section for the interpretation of this result). Login to comment
107 As shown in the lower panel of Fig. 3B, GFP-WT-CFTR was co-immunoprecipitated efficiently with the wild-type DNAJB12 but not with the H139Q mutant, indicating that the HPD motif in the J-domain of DNAJB12 is important for the efficient binding Fig. 2. Login to comment
117 (A) HeLa cells were mock-transfected or transfected with a plasmid to express DNAJB12-Flag or DNAJB12 H139Q-Flag. Login to comment
183 This association was abolished by a mutation (H139Q) in the J-domain of DNAJB12 (Fig. 3A, B). Login to comment

[hide] Heterogeneous spectrum of mutations in CFTR gene f... Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23. Sharma H, Mavuduru RS, Singh SK, Prasad R
Heterogeneous spectrum of mutations in CFTR gene from Indian patients with congenital absence of the vas deferens and their association with cystic fibrosis genetic modifiers.
Mol Hum Reprod. 2014 Sep;20(9):827-35. doi: 10.1093/molehr/gau047. Epub 2014 Jun 23., [PMID:24958810]

Abstract [show]
Cystic fibrosis (CF) is usually considered a rare disease in the Indian population. Two studies have reported on the frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Indian males with congenital absence of the vas deferens (CAVD), however, data on the spectrum of CFTR gene mutations are still lacking. Therefore, the present study was designed to identify the spectrum of CFTR gene mutations as well as to investigate an association of CF genetic modifiers in the penetrance of CAVD in infertile Indian men. A total of 60 consecutive infertile males with a diagnosis of CAVD were subjected to CFTR gene analysis which revealed 13 different CFTR gene mutations and 1 intronic variant that led to aberrant splicing. p.Phe508del (n = 16) and p.Arg117His (n = 4) were among the most common severe forms of CFTR mutations identified. The IVS8-T5 allele, which is considered as a mild form of CFTR mutation, was found with an allelic frequency of 28.3%. Eight novel mutations were also identified in the CFTR gene from our patient cohort. It is noteworthy that the spectrum of CFTR gene mutation is heterogeneous, with exon 4 and exon 11 as hot spot regions. Moreover, we also found an association of the CF genetic modifiers, viz., transforming growth factor (TGF)-beta1 and endothelial receptor type-A (EDNRA) genes with the CAVD phenotype. The findings are of considerable clinical significance because men suffering from infertility due to CAVD can decide to use artificial reproduction technology. The children of men with CAVD are at risk of carrying CFTR mutations; therefore, genetic counseling is a crucial step for such patients. With special reference to developing countries, such as India, where whole gene sequencing is not feasible, the outcome of our study will make the screening procedure for CFTR gene simpler and more cost-effective as we have identified hot spot regions of the CFTR gene which are more prone to mutation in Indian males with CAVD. Moreover, this is the first study from the Indian population to investigate the association of CF genetic modifiers with penetrance of the CAVD phenotype. The observed association of the genetic modifiers TGF-beta1 and EDNRA in the penetrance of CAVD further supports their involvement in genesis of the vas deferens.

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82 SSCP analysis and subsequent DNA sequencing further revealed eleven mutations, viz., p.Gly480Ser, p.Ser549Asn, p.Arg518Lys, p.Gly126Cys, p.Ala141Gly, p.His139Gln, p.Ser118Pro, p.Arg170Cys, p.Glu585Gln, p.Met281Arg, p.Arg933Thr and two intronic variants c.1679+24G.T, c.1766+48G.C. Login to comment
94 Genotype Number of CAVD subjects (n 5 60) Number of healthy controls (n 5 50) p.Phe508del/U 11 ND p.Phe508del/5T 5 ND 5T/5T 8 ND 5T/U 9 7 p.Arg117His/7T 2 ND p.Arg117His/5T 2 ND p.Arg933Thr/U 1 ND p.His139Gln/U 1 ND p.Ser118Pro/c. Login to comment
147 Among the eight novel mutations identified, p.Ser118Pro, p.Met281Arg, p.Gly126Cys, p.Arg933Thr were predicted to be damaging, whereas p.Arg518Lys, p.Ala141Gly, p.His139Gln, p.Glu585Gln were possibly neutral mutations (http://genetics.bwh.harvard.edu/ pph2/). Login to comment

[hide] Function, pharmacological correction and maturatio... J Cyst Fibros. 2015 Jan;14(1):34-41. doi: 10.1016/j.jcf.2014.06.008. Epub 2014 Jul 16. Sharma H, Jollivet Souchet M, Callebaut I, Prasad R, Becq F
Function, pharmacological correction and maturation of new Indian CFTR gene mutations.
J Cyst Fibros. 2015 Jan;14(1):34-41. doi: 10.1016/j.jcf.2014.06.008. Epub 2014 Jul 16., [PMID:25042876]

Abstract [show]
BACKGROUND: Cystic fibrosis (CF) is rare in India. Most CF mutations identified are not yet functionally characterized. Hence, genetic counseling and adoption of therapeutic approach are particularly difficult. Our aim was to study the function and maturation of a spectrum of eleven Indian CFTR mutations from classical CF and infertile male patients with CBAVD. METHODS: We used Western blot, pharmacology and iodide efflux to study CFTR maturation and chloride transport in BHK cells expressing pEGFP-CFTR constructs for L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E. RESULTS: Among these CFTR mutants, only L69H is not processed as a c-band and not functional at 37 degrees C. However, the functions of L69H and S549N and the maturation of L69H are corrected at 27 degrees C and by the investigational drug VX809. CONCLUSION: These data should help in developing counseling and therapeutic approaches in India. We identified L69H as a novel class II CF mutation.

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4 Methods: We used Western blot, pharmacology and iodide efflux to study CFTR maturation and chloride transport in BHK cells expressing pEGFP-CFTR constructs for L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E. Login to comment
33 Because the cellular and functional data on these mutations can improve CF genetic counseling, we examined here the functional and cellular consequences of eleven rare missense mutations, L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E present in CFTR gene from both classical CF patients and CBAVD patients, which have been detected during molecular diagnosis of Indian CF patients (Fig. 1). Login to comment
44 The activation of nine CFTR mutants F87I, S118P, G126S, H139Q, F157C, F494L, E543A, Y852F and D1270E was not significantly different from WT-CFTR (Fig. 3A for example of traces and Fig. 3B for a summary). Login to comment
49 Mutation Nucleotide change Location in CFTR Patient phenotype CFTR dysfunction L69H T to A at 338 N-terminal Patient 1: Pancreatic insufficient, sweat chloride N 60 mEq/L, S. aureus positive; Patient 2: CBAVD Defective CFTR maturation and channel activity, class-II CF mutation F87I T to A at 391 MSD1 CBAVD No dysfunction S118P T to C at 484 MSD1 CBAVD No dysfunction G126S G to A at 508 MSD1 CBAVD No dysfunction H139Q C to G at 549 MSD1 CBAVD No dysfunction F157C T to G at 602 MSD1 CBAVD No dysfunction F494L T to C at 1612 NBD1 CBAVD No dysfunction E543A A to C at 1760 NBD1 CBAVD No dysfunction S549N G to A at 1778 NBD1 Patient 1: Frequent respiratory infection. Login to comment
70 Discussion The present study investigated the potential deleterious functional consequence of novel rare missense mutations 0 2 4 6 8 0.0 0.1 0.2 0.3 WT F87I S118P H139Q F157C NT Time (min) k (min -1 ) 0 2 4 6 8 0.0 0.1 0.2 0.3 G126S S549N Y852F WT F508del L69H Time (min) k (min -1 ) 0 2 4 6 8 0.0 0.1 0.2 0.3 WT F508del F494L D1270E NT E543A Time (min) k (min -1 ) W T F 8 7 I S 1 1 8 P G 1 2 6 S H 1 3 9 Q F 1 5 7 C F 4 9 4 L E 5 4 3 A Y 8 5 2 F D 1 2 7 0 E S 5 4 9 N L 6 9 H F 5 0 8 d e l 0.0 0.5 1.0 1.5 2.0 ns *** *** *** *** ns (k peak - k basal) mutant / (k peak - k basal) WT A B Fig. 3. Login to comment
72 Iodide efflux experiments in transfected BHK-21 cells, WT-CFTR, L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E. Login to comment
100 In our study, the eleven CFTR mutants i.e. L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E produced different results. Login to comment
121 The functional characterization of nine other novel mutations associated with CBAVD viz., F87I, S118P, G126S, H139Q, F157C, F494L, E543A, Y852F and D1270E revealed that these mutants did not cause any effect on normal CFTR maturation process and Cl-channel activity. Login to comment
129 Patients profile Eleven rare missense mutations i.e. L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F, and D1270E were characterized by using single stranded conformation polymorphism and subsequently by DNA sequencing in Indian infertile CBAVD male patients [7,8]. Login to comment
138 The remaining all nine mutations viz., G126S, Y852F, F87I, S118P, H139Q, F157C, F494L, E543A, and D1270E were identified in Indian infertile males diagnosed with only CBAVD. Login to comment