A novel mutation (−195C&gt;A) in the promoter region of CFTR gene is associated with Chinese Congenital Bilateral Absence of Vas Deferens (CBAVD)

Feng, Jiarong; Wu, Xiao; Zhang, Yanan; Yang, Xinggang; Ma, Gongchao; Chen, Shitao; Luo, Shaoge; Zhang, Yan

doi:10.1016/j.gene.2019.144007

Cited by 14 publications

(12 citation statements)

References 33 publications

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“…These conditions that do not meet all the criteria for cystic fibrosis but are related to CFTR dysfunction have been grouped under the generic term CFTR-RD (Bombieri et al 2011 ). All regions of CFTR can be affected by disease-causing mutations including promoter regions and deep intronic regions (Feng et al 2019 ; Bergougnoux et al 2019 ). Depending on their effects on the biogenesis and functions of CFTR, pathogenic alleles are classified into two main categories: CF-causing variants (also called "severe") which, in the homozygous state, are always associated with CF and non-CF-causing variants which have never been observed in CF patients and which are, therefore, mistakenly called "mild" alleles.…”

Section: Genetics Of Cavdmentioning

confidence: 99%

Genetics of the congenital absence of the vas deferens

2020

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Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other CFTR-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.

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Section: Genetics Of Cavdmentioning

confidence: 99%

Genetics of the congenital absence of the vas deferens

2020

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“…Up to now, more than 2000 mutations have been reported in this gene (http://www.genet.sickkids.on.ca/). Disease causing mutations in CFTR may affect not only coding regions but also the promoter and deep intronic regions [67,68]. CFTR disease-causing alleles can be classified into two main types: (i) "severe" or CF-causing mutations, which are always associated with CF in a homozygous state; (ii) "mild" or non-CF-causing mutations, which have never been observed in CF patients.…”

Section: Congenital Bilateral Absence Of Vas Deferens (Cbavd)mentioning

confidence: 99%

Genetics of Azoospermia

Cioppi

Rosta

Krausz

2021

IJMS

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Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients.

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“…Indeed, the c.-165G>A promoter mutation enhanced FOXI1 binding, thereby inhibiting transcription of the CFTR gene. Feng et al (53) recently demonstrated that the c.-195C>A promoter mutation significantly enhanced the inhibitory effect of specificity protein (SP) on CFTR expression.…”

Section: Hotspot Mutation Types In Patients With Cbavdmentioning

confidence: 99%

Section: Hotspot Mutation Types In Patients With Cbavdmentioning

confidence: 99%

“…Promoters regulate gene transcription levels by interacting with trans -acting factors ( 17 , 53 ). The CFTR gene promoter is a housekeeping-type, GC-rich (<65% GC content) promoter lacking the typical TATA box, and its specific cis -acting element location and regulatory mechanism are poorly characterized ( 53 ). Yoshimura et al ( 54 ) suggested that the core sequence of the CFTR gene promoter may be located ~3.8 kb upstream of the ATG transcription initiation site and contains conserved sequences acting as binding sites for several important transcription proteins, such as CTCC-binding factor (CTCF), activator protein-1 (AP-1), specificity protein 1 (SP1), greater curvature (GRE), carbapenem-resistant (CRE), CCAAT/enhancer-binding protein (C/EBP) and Y-box proteins ( 55 ).…”

Section: Hotspot Mutation Types In Patients With Cbavdmentioning

confidence: 99%

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Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review)

Cui¹,

Wu²,

Li³

et al. 2020

Mol Med Rep

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congenital bilateral absence of the vas deferens (cBaVd) is predominantly caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. cBaVd accounts for 2-6% of male infertility cases and up to 25% of cases of obstructive azoospermia. With the use of pre-implantation genetic diagnosis, testicular or epididymal sperm aspiration, intracytoplasmic sperm injection and in vitro fertilization, patients affected by cBaVd are able to have children who do not carry CFTR gene mutations, thereby preventing disease. Therefore, genetic counseling should be provided to couples receiving assisted reproductive techniques to discuss the impact of CFTR gene mutations on reproductive health. In the present article, the current literature concerning the CFTR gene and its association with CBAVD is reviewed. Contents 1. Introduction 2. Overview of CFTR structure and function 3. The CFTR gene and development of the vas deferens 4. The CFTR gene in patients with CBAVD 5. Hotspot mutation types in patients with CBAVD 6. Assisted reproductive techniques and genetic counselling 7. Conclusions

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A novel mutation (−195C>A) in the promoter region of CFTR gene is associated with Chinese Congenital Bilateral Absence of Vas Deferens (CBAVD)

Cited by 14 publications

References 33 publications

Genetics of the congenital absence of the vas deferens

Genetics of the congenital absence of the vas deferens

Genetics of Azoospermia

Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review)

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