Artículo

Bruque, C.D.; Delea, M.; Fernández, C.S.; Orza, J.V.; Taboas, M.; Buzzalino, N.; Espeche, L.D.; Solari, A.; Luccerini, V.; Alba, L.; Nadra, A.D.; Dain, L. "Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations" (2016) Scientific Reports. 6
Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for 90-95% of CAH cases. In this work we performed an extensive survey of mutations and SNPs modifying the coding sequence of the CYP21A2 gene. Using bioinformatic tools and two plausible CYP21A2 structures as templates, we initially classified all known mutants (n = 343) according to their putative functional impacts, which were either reported in the literature or inferred from structural models. We then performed a detailed analysis on the subset of mutations believed to exclusively impact protein stability. For those mutants, the predicted stability was calculated and correlated with the variant's expected activity. A high concordance was obtained when comparing our predictions with available in vitro residual activities and/or the patient's phenotype. The predicted stability and derived activity of all reported mutations and SNPs lacking functional assays (n = 108) were assessed. As expected, most of the SNPs (52/76) showed no biological implications. Moreover, this approach was applied to evaluate the putative synergy that could emerge when two mutations occurred in cis. In addition, we propose a putative pathogenic effect of five novel mutations, p.L107Q, p.L122R, p.R132H, p.P335L and p.H466fs, found in 21-hydroxylase deficient patients of our cohort. © The Author(s) 2016.

Registro:

Documento: Artículo
Título:Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations
Autor:Bruque, C.D.; Delea, M.; Fernández, C.S.; Orza, J.V.; Taboas, M.; Buzzalino, N.; Espeche, L.D.; Solari, A.; Luccerini, V.; Alba, L.; Nadra, A.D.; Dain, L.
Filiación:Centro Nacional de Genética Médica, ANLIS, Buenos Aires, Argentina
Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
Consultorio y Laboratorio de Genética, Rosario, Argentina
Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina
Laboratorio de Cultivo Celular y Medicina Regenerativa, Servicio de Ortopedia y Traumatología, Hospital de Agudos Juan A. Fernández, Buenos Aires, Argentina
Palabras clave:CYP21A2 protein, human; steroid 21 monooxygenase; chemistry; computer simulation; congenital adrenal hyperplasia; genetic variation; genetics; human; metabolism; molecular model; mutation; protein conformation; protein stability; single nucleotide polymorphism; structure activity relation; Adrenal Hyperplasia, Congenital; Computer Simulation; Genetic Variation; Humans; Models, Molecular; Mutation; Polymorphism, Single Nucleotide; Protein Conformation; Protein Stability; Steroid 21-Hydroxylase; Structure-Activity Relationship
Año:2016
Volumen:6
DOI: http://dx.doi.org/10.1038/srep39082
Título revista:Scientific Reports
Título revista abreviado:Sci. Rep.
ISSN:20452322
CAS:steroid 21 monooxygenase, 9029-68-9; CYP21A2 protein, human; Steroid 21-Hydroxylase
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_20452322_v6_n_p_Bruque

Referencias:

  • New, M.I., White, P.C., Pang Dupont S, B., Speiser, P.W., The Adrenal Hyperplasias in (1989) The Metabolic Basis of Inherited Disease, pp. 1881-1917. , (eds Scriver, C. R., Beaudet, A. L., Sly, S. & Valle, D.), McGraw-Hill
  • Miller, W.L., Clinical review 54: Genetics, diagnosis, and management of 21-hydroxylase deficiency (1994) J. Clin. Endocrinol. Metab, 78, pp. 241-246
  • Pang, S., Shook, M.K., Current status of neonatal screening for congenital adrenal hyperplasia (1997) Curr. Opin. Pediatr, 9, pp. 419-423
  • Koppens, P.F., Family studies of the steroid 21-hydroxylase and complement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in the Netherlands (1992) Eur. J. Pediatr, 151, pp. 885-892
  • Blanchong, C.A., Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RPC4- CYP21-TNX (RCCX) modules in caucasians. the load of RCCX genetic diversity on major histocompatibility complexassociated disease (2000) J. Exp. Med, 191, pp. 2183-2196
  • Donohoue, P.A., Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein (1986) J. Clin. Endocrinol. Metab, 62, pp. 995-1002
  • Higashi, Y., Tanae, A., Inoue, H., Fujii-Kuriyama, Y., Evidence for frequent gene conversion in the steroid 21-hydroxylase P-450(C21) gene: Implications for steroid 21-hydroxylase deficiency (1988) Am. J. Hum. Genet, 42, pp. 17-25
  • White, P.C., Speiser, P.W., Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2000) Endocr. Rev, 21, pp. 245-291
  • Nelson, D.R., Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants (2004) Pharmacogenetics, 14, pp. 1-18
  • Kominami, S., Ochi, H., Kobayashi, Y., Takemori, S., Studies on the steroid hydroxylation system in adrenal cortex microsomes. Purification and characterization of cytochrome P-450 specific for steroid C-21 hydroxylation (1980) J. Biol. Chem, 255, pp. 3386-3394
  • Higashi, Y., Yoshioka, H., Yamane, M., Gotoh, O., Fujii-Kuriyama, Y., Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: A pseudogene and a genuine gene (1986) Proc. Natl. Acad. Sci. USA, 83, pp. 2841-2845
  • White, P.C., New, M.I., Dupont, B., Structure of human steroid 21-hydroxylase genes (1986) Proc. Natl. Acad. Sci. USA, 83, pp. 5111-5115
  • Robins, T., Carlsson, J., Sunnerhagen, M., Wedell, A., Persson, B., Molecular model of human CYP21 based on mammalian CYP2C5: Structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia (2006) Mol. Endocrinol, 20, pp. 2946-2964
  • Pey, A.L., Stricher, F., Serrano, L., Martinez, A., Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases (2007) Am. J. Hum. Genet, 81, pp. 1006-1024
  • Alibés, A., Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example (2010) Nucleic Acids Res, 38, pp. 7422-7431
  • Minutolo, C., Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients (2011) PLoS One, 6
  • Worth, C.L., Preissner, R., Blundell, T.L., SDM-a server for predicting effects of mutations on protein stability and malfunction (2011) Nucleic Acids Res, 39, pp. W215-W222
  • Zhao, B., Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants (2012) J. Biol. Chem, 287, pp. 10613-10622
  • Pallan, P.S., Human Cytochrome P450 21A2, the Major Steroid 21-Hydroxylase: Structure of the enzyme progesterone substrate complex and rate-limiting C-H bond cleavage (2015) J. Biol. Chem, 290, pp. 13128-13143
  • Haider, S., Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia (2013) Proc. Natl. Acad. Sci. USA, 110, pp. 2605-2610
  • Brønstad, I., Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia (2014) Endocr. Connect, 3, pp. 67-74
  • Massimi, A., Functional and Structural Analysis of Four Novel Mutations of CYP21A2 Gene in Italian Patients with 21-Hydroxylase Deficiency (2014) Horm. Metab. Res, 46, pp. 515-520
  • Taboas, M., Functional studies of p.R132C, p.R149C, p.M283V, p.E431K, and a novel c.652-2A> G mutations of the CYP21A2 gene (2014) PLoS One, 9
  • Barbaro, M., In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia (2014) Clin. Endocrinol. (Oxf), 82, pp. 37-44
  • Rodrigues, N.R., Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene from an individual with congenital adrenal hyperplasia (1987) EMBO J, 6, pp. 1653-1661
  • Tardy, V., Gene symbol: CYP21A2. Disease: Steroid 21-hydroxylase deficiency (2006) Hum. Genet, 119, p. 363
  • Tardy, V.T.V., Morel, Y., Gene symbol: CYP21A2 (2007) Hum. Genet, 121, p. 293
  • Tardy, V.T.V., Gene symbol: CYP21A2 (2007) Hum. Genet, 121, pp. 292-293
  • Wang, R., 21-Hydroxylase deficiency-induced congenital adrenal hyperplasia in 230 Chinese patients: Genotype-phenotype correlation and identification of nine novel mutations (2016) Steroids, 108, pp. 47-55
  • New, M.I., Genotype-phenotype correlation in 1, 507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency (2013) Proc. Natl. Acad. Sci. USA, 110, pp. 2611-2616
  • Milacic, I., Molecular genetic study of congenital adrenal hyperplasia in Serbia: Novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations (2015) J. Endocrinol. Invest, 38, pp. 1199-1210
  • Vrzalová, Z., Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency (2010) Int. J. Mol. Med, 26, pp. 595-603
  • Speiser, P.W., New, M.I., White, P.C., Molecular Genetic Analysis of Nonclassic Steroid 21-Hydroxylase Deficiency Associated with HLA-B14, DR1 (1988) N. Engl. J. Med, 319, pp. 19-23
  • Kirac, D., The Frequency and the Effects of 21-Hydroxylase Gene Defects in Congenital Adrenal Hyperplasia Patients (2014) Ann. Hum. Genet, 78, pp. 399-409
  • Concolino, P., Mello, E., Zuppi, C., Capoluongo, E., Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: An update of new CYP21A2 mutations (2010) Clin. Chem. Lab. Med, 48, pp. 1057-1062
  • Loke, K.Y., Lee, Y.S., Lee, W.W., Poh, L.K., Molecular analysis of CYP-21 mutations for congenital adrenal hyperplasia in Singapore (2001) Horm. Res, 55, pp. 179-184
  • Ezquieta, B., Non-classical 21-hydroxylase deficiency in children: Association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations (2002) Acta Paediatr, 91, pp. 892-898
  • Stikkelbroeck, N.M.M.L., CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in the Netherlands: Six novel mutations and a specific cluster of four mutations (2003) J. Clin. Endocrinol. Metab, 88, pp. 3852-3859
  • Deneux, C., Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2001) J. Clin. Endocrinol. Metab, 86, pp. 207-213
  • Bojunga, J., Structural and functional analysis of a novel mutation of CYP21B in a heterozygote carrier of 21-hydroxylase deficiency (2005) Hum. Genet, 117, pp. 558-564
  • Wasniewska, M., Novel mutation of CYP21A2 gene (N387K) affecting a non-conserved amino acid residue in exon 9 (2009) J Endocrinol Invest, 32, p. 633
  • Baradaran-Heravi, A., Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran (2007) Clin. Endocrinol. (Oxf), 67, pp. 335-341
  • Jiang, L., Identification and functional characterization of a novel mutation P459H and a rare mutation R483W in the CYP21A2 gene in two Chinese patients with simple virilizing form of congenital adrenal hyperplasia (2012) J. Endocrinol. Invest, 35, pp. 485-489
  • Nadra, A.D., Serrano, L., Alibés, A., DNA-binding specificity prediction with FoldX (2011) Methods in Enzymology, 498, pp. 3-18
  • Wu, D.A., Chung, B., Mutations of P45Oc21 (Steroid 21-Hydroxylase) at Cys428, Val281, and Serf " Result in Complete, Partial, or No Loss of Enzymatic Activity, Respectively (1991) J. Clin. Invest, 88, pp. 519-523
  • Ozturk, I.C., Wei, W.-L., Palaniappan, L., Rubenfire, M., Killeenas, A.A., Analysis of CYP21 Coding Polymorphisms in Three Ethnic Populations: Further Evidence of Nonamplifying CYP21 Alleles among Whites (2000) Mol. Diagnosis, 5, pp. 47-52
  • Asanuma, A., Molecular analysis of Japanese patients with steroid 21-hydroxylase deficiency (1999) J. Hum. Genet, 44, pp. 312-317
  • Dolzan, V., Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia (2005) Eur. J. Endocrinol, 153, pp. 99-106
  • Nikoshkov, A., Lajic, S., Holst, M., Wedell, A., Luthman, H., Synergistic effect of partially inactivating mutations in steroid 21-hydroxylase deficiency (1997) J. Clin. Endocrinol. Metab, 82, pp. 194-199
  • Menassa, R., P.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency (2008) J. Clin. Endocrinol. Metab, 93, pp. 1901-1908
  • Tardy, V., Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier (2010) J. Clin. Endocrinol. Metab, 95, pp. 1288-1300
  • Sherry, S.T., DbSNP: The NCBI database of genetic variation (2001) Nucleic Acids Res, 29, pp. 308-311
  • Sudmant, P.H., An integrated map of structural variation in 2, 504 human genomes (2015) Nature, 526, pp. 75-81
  • Sali, A., Blundell, T.L., Comparative protein modelling by satisfaction of spatial restraints (1993) J. Mol. Biol, 234, pp. 779-815
  • Tamura, K., Dudley, J., Nei, M., Kumar, S., MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0 (2007) Mol. Biol. Evol, 24, pp. 1596-1599
  • Shen, M.-Y., Sali, A., Statistical potential for assessment and prediction of protein structures (2006) Protein Sci, 15, pp. 2507-2524
  • Benkert, P., Biasini, M., Schwede, T., Toward the estimation of the absolute quality of individual protein structure models (2011) Bioinformatics, 27, pp. 343-350
  • Ramachandran, G.N., Ramakrishnan, C., Sasisekharan, V., Stereochemistry of polypeptide chain configurations (1963) J. Mol. Biol, 7, pp. 95-99
  • Schymkowitz, J., The FoldX web server: An online force field (2005) Nucleic Acids Res, 33, pp. W382-W388
  • Soardi, F.C., Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients (2008) J Clin Endocrinol Metab, 93, pp. 2416-2420
  • Speiser, P.W., Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society clinical practice guideline (2010) J Clin Endocrinol Metab, 95, pp. 4133-4160

Citas:

---------- APA ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., Espeche, L.D.,..., Dain, L. (2016) . Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations. Scientific Reports, 6.
http://dx.doi.org/10.1038/srep39082
---------- CHICAGO ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., et al. "Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations" . Scientific Reports 6 (2016).
http://dx.doi.org/10.1038/srep39082
---------- MLA ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., et al. "Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations" . Scientific Reports, vol. 6, 2016.
http://dx.doi.org/10.1038/srep39082
---------- VANCOUVER ----------
Bruque, C.D., Delea, M., Fernández, C.S., Orza, J.V., Taboas, M., Buzzalino, N., et al. Structure-based activity prediction of CYP21A2 stability variants: A survey of available gene variations. Sci. Rep. 2016;6.
http://dx.doi.org/10.1038/srep39082