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Cystic fibrosis transmembrane conductance regulator (CFTR) gene abnormalities in Indian males with congenital bilateral absence of vas deferens & renal anomalies

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      Abstract

      Background & objectives:

      The role of cystic fibrosis transmembrane conductance regulator ( CFTR) gene mutations in congenital bilateral absence of vas deferens and unilateral renal agenesis (CBAVD-URA) has been controversial. Here, we report the cases of five Indian males with CBAVD-URA. The objective was to evaluate the presence or absence of CFTR gene mutations and variants in CBAVD-URA. The female partners of these males were also screened for cystic fibrosis (CF) carrier status.

      Methods:

      Direct DNA sequencing of CFTR gene was carried out in five Indian infertile males having CBAVD-URA. Female partners (n=5) and healthy controls (n=32) were also screened.

      Results:

      Three potential regulatory CFTR gene variants (c.1540A>G, c.2694T>G and c.4521G>A) were detected along with IVS8-5T mutation in three infertile males with CBAVD-URA. Five novel CFTR gene variants (c.621+91A>G, c.2752+106A>T, c.2751+85_88delTA, c.3120+529InsC and c.4375-69C>T), four potential regulatory CFTR gene variants (M470V, T854T, P1290P, Q1463Q) and seven previously reported CFTR gene variants (c.196+12T>C, c.875+40A>G, c.3041-71G>C, c.3271+42A>T, c.3272-93T>C, c.3500-140A>C and c.3601-65C>A) were detected in infertile men having CBAVD and renal anomalies

      Interpretation & conclusions:

      Based on our findings, we speculate that CBAVD-URA may also be attributed to CFTR gene mutations and can be considered as CFTR-related disorder (CFTR-RD). The CFTR gene mutation screening may be offered to CBAVD-URA men and their female partners undergoing ICSI. Further studies need to be done in a large sample to confirm the findings.

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      Most cited references 19

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      Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.

      It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.
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        Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.

        In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.
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          Imaging of the seminal vesicle and vas deferens.

          The seminal vesicle (SV) and vas deferens (VD) are ancillary but essential urogenital organs. Understanding their embryologic features and anatomy can be helpful in evaluating various disorders of these organs. Recently, cross-sectional imaging modalities, including ultrasonography, computed tomography, and magnetic resonance (MR) imaging, have been increasingly used for evaluation of the SV and VD. The development of these organs is closely related to that of urinary organs, including the kidneys and ureters. Frequently, unilateral SV agenesis is associated with renal agenesis, and bilateral SV or VD agenesis is associated with mutations of the cystic fibrosis gene. Congenital SV cysts are commonly associated with ipsilateral renal agenesis or dysgenesis. These congenital anomalies can be well evaluated with MR imaging. Inflammation, post-radiation therapy changes, and amyloidosis of the SV appear as diffuse wall thickening and may mimic tumor invasion by prostate cancer. Primary neoplasms involving the SV and VD are extremely rare, whereas secondary neoplasms are much more common. Carcinoma from the prostate, bladder, or rectum can directly invade the SV and VD. Typical MR imaging findings of such invasion include a low-signal-intensity mass on T2-weighted images or soft-tissue thickening in the SV or VD along with loss of normal architecture.
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            Author and article information

            Affiliations
            [1 ] Department of Reproductive Endocrinology & Infertility, National Institute for Research in Reproductive Health (ICMR), Mumbai, India
            [2 ] Department of Gamete Immunobiology, National Institute for Research in Reproductive Health (ICMR), Mumbai, India
            [3 ] Saint Vincent Hospital, Worcester, USA
            [4 ] Lilavati Hospital & Research Center, Mumbai, India
            [5 ] Sudha Hospital, Erode, India
            Author notes
            Reprint requests: Dr Rahul Gajbhiye, Department of Reproductive Endocrinology & Infertility, National Institute for Research in Reproductive Health (ICMR), J.M. Street, Parel, Mumbai 400 012, Maharashtra, India e-mail: gajbhiyer@ 123456nirrh.res.in
            Journal
            Indian J Med Res
            Indian J. Med. Res
            IJMR
            The Indian Journal of Medical Research
            Medknow Publications & Media Pvt Ltd (India )
            0971-5916
            May 2016
            : 143
            : 5
            : 616-623
            27488005 4989835 IJMR-143-616 10.4103/0971-5916.187110
            Copyright: © Indian Journal of Medical Research

            This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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