High frequency of splice site mutation in 21-hydroxylase deficiency children

Sharaf, Sahar A.; Hafez, Mona; ElAbd, D.; Ahmed, Ismail; Thabet, G.; Elsharkawy, Marwa

doi:10.1007/s40618-014-0207-1

Cited by 5 publications

(5 citation statements)

References 32 publications

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“…Some P450 SNPs are exceedingly rare, occurring in less than 1% of the population. These rare mutations are linked to congenital defects, including glaucoma (CYP1B1; Stoilov et al, 1998;Tanwar et al, 2009;Sheikh et al, 2014), 17-a hydroxylase deficiency (CYP17A1; Yamaguchi et al, 1998;Costa-Santos et al, 2004;Hwang et al, 2011;Qiao et al, 2011), congenital adrenal hyperplasia (CYP21A2; Robins et al, 2006;Lee, 2013;Szabó et al, 2013;Sharaf et al, 2015), spina bifida (CYP26A1; Rat et al, 2006), focal facial dermal dysplasia (CYP26C1; Slavotinek et al, 2013), and cerebrotendinous xanthomatosis (CYP27A1; Garuti et al, 1996;Verrips et al, 1997;Chen et al, 1998;Tian and Zhang, 2011). Other P450 polymorphisms that alter splicing are associated with neurologic and metabolic diseases, including Parkinson's disease (CYP2D6, Denson et al, 2005;CYP2J2, Searles Nielsen et al, 2013), hypertension (CYP4A11, Zhang et al, 2013;CYP17A1, Wang et al, 2011), breast cancer (CYP2D6, Huang et al, 1996;CYP19A1, Kristensen et al, 2000;) colon cancer (CYP2W1, Stenstedt et al, 2012), and lung cancer (CYP2D6, Huang et al, 1997;CYP2F1, Tournel et al, 2007).…”

Section: Snp-sensitive Alternative Splicing In the Cytochrome P450 Sumentioning

confidence: 99%

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

2017

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The human genome encodes 57 cytochrome P450 genes, whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics, and unknown numbers of endogenous compounds, including steroids, retinoids, and eicosanoids. Indeed, P450 genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several National Institutes of Health databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human P450 transcriptome. This review describes a remarkable diversification of the 57 human P450 genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's P450 proteome. Important P450 splice variants from families 1A, 1B, 2C, 2D, 3A, 4F, 19A, and 24A have now been documented, with some displaying alternative subcellular distribution or catalytic function directly linked to a disease pathology. The expansion of P450 transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, -splicing between gene transcripts, single-nucleotide polymorphisms, and epigenetic regulation of alternate splicing. Homeostatic regulation of variant P450 expression is influenced also by nuclear receptor signaling, suppression of nonsense-mediated decay or premature termination codons, mitochondrial dysfunction, or host infection. This review focuses on emergent aspects of the adaptive gene-splicing process, which when viewed through the lens of P450-nuclear receptor gene interactions, resembles a primitive immune-like system that can rapidly monitor, respond, and diversify to acclimate to fluctuations in endo-xenobiotic exposure. Insights gained from this review should aid future drug discovery and improve therapeutic management of personalized drug regimens.

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Section: Snp-sensitive Alternative Splicing In the Cytochrome P450 Sumentioning

confidence: 99%

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

2017

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“…It was observed that about 65-75 % of the patients with CAH are compound heterozygotes [8]. Also, the most severe mutations (such as c.290-13A/C>G, c.515T>A and del c.329_336del) were not found among healthy controls [9] showing that genetic variants causing the most severe form of CAH are rare in general population.…”

Section: Introductionmentioning

confidence: 99%

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

Milacic

Barać

Milenković

et al. 2015

J Endocrinol Invest

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“…In 2014, Sharaf et al . [ 19 ] analyzed I2G mutation by allele-specific PCR and reported 76% and 17.2% cases with heterozygous and homozygous mutation respectively. Another study in Macedonia population report 41.5% of patient with I2G mutation by PCR/ACRS method.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately, 65–70% of CYP21A2 mutations are deleterious and due to microconversion derived from pseudogene CYP21A1P [ 18 ] including eight common mutations (p.P30L, c. 293-13A/C >G in intron 2 splice site, 8-bp deletion in exon 3, p.I172L, exon 6 cluster [p.I236N, p.V237E, p.M239K], p.V281L, p.Q318X, p.R356W). [ 19 ] About 25–30% are caused by unequal meiotic crossovers (or deletions). [ 18 ] Point mutations in compound state indicates SW form, although a single mutation has mild effect.…”

Section: Introductionmentioning

confidence: 99%

Mutation detection of CYP21A2 gene in nonclassical congenital adrenal hyperplasia patients with premature pubarche

et al. 2016

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Background:Congenital adrenal hyperplasia (CAH) due to mutations in the gene encoding 21-hydroxilase is one of common disease with an autosomal recessive form. In this study, our aim is to detect the prevalence of eight common mutations in nonclassical congenital adrenal hyperplasia (NCAH).Materials and Methods:A total of 30 patients with clinical and laboratory evidence of NCAH was selected. Gene-specific polymerase chain reaction (PCR) without contamination of pseudogene was carried out, and PCR product of this step was used to amplification-refractory mutation system PCR on eight common mutations in CYP21A2 gene.Results:Two heterozygote patients for I2G mutation and six heterozygote patients for Q318X mutation is reported in our study. These mutations associated with the classic form of CAH, and heterozygotes presented with NC symptom, including premature pubarche and hirsutism.Conclusion:There are some data about the association of the mutation with the clinical form of CAH including classic (salt-wasting and simple virilizing) and NC form. I2G and Q318X mutations were reported in classic form in homozygote state, but the heterozygote form associated with NC form. CAH diagnosis with NC symptom and with measurement of 17-hydroxyprogestrone as NCAH is not a trusted assessment and require to molecular analysis for accurate diagnosis.

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High frequency of splice site mutation in 21-hydroxylase deficiency children

Abstract: The genetic analysis of the splice site mutation c.293-13A>G and c.518T>A variant can be used as good biomarkers for early detection of cases and carriers in 21-OHD CAH Egyptian children, since the methods used have rapid turnaround time.

Cited by 5 publications

References 32 publications

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism

Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations

Mutation detection of CYP21A2 gene in nonclassical congenital adrenal hyperplasia patients with premature pubarche

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