Steroid 21-hydroxylase deficiency: two additional mutations in salt-wasting disease and rapid screening of disease-causing mutations
Abstract
A method for genetic diagnosis of steroid 21-hydroxylase deficiency was developed based on allele-specific PCR. With this approach, genotyping of fourteen mutations and diagnosis of homozygous gene deletions can be performed within hours from tissue sampling. One patient with salt-wasting disease had normal genotype at all positions screened. DNA sequencing revealed two novel mutations, a G to C transversion at the conserved splice donor site of intron 7 and a TGG to TAG nonsense mutation at Trp 406 in exon 9. Allele-specific PCR was established also for these mutations and used to screen for their presence in the pseudogene. However, the two novel mutations were not found in at least 34 pseudogenes.
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Other rare alleles, which are true mutations rather than gene conversions, have been described in single individuals.
“Other rare alleles, which are true mutations rather than gene conversions, have been described in single individuals (436 -440).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [438]
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458 · see citing works
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency*
White, P. C., & Speiser, P. W. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.3.0398 · Cited by 1,432 · see citing works
Øyvind Øverli, A., Sørensen, C., Pulman, K. G. T., Pottinger, T. G., Korzan, W. J., Summers, C. H., & Nilsson, G. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.10.006 · Cited by 503 · see citing works
“A multitude of genetic polymorphisms are known in this pathway in humans (see e.g. Wedell and Luthman, 1993; Stratakis and Rennert, 1999), which are all connected with debilitations in untreated patients.”
BackgroundWedell, A. (1994) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.78.5.1145 · Cited by 370 · see citing works
Self-citationTherrell, B. L., Berenbaum, S. A., Manter-Kapanke, V., Simmank, J., Korman, K., Prentice, L., Gonzalez, J., & Gunn, S. (1998) · Pediatrics · doi:10.1542/peds.101.4.583 · Cited by 344 · see citing works
Genetics of congenital adrenal hyperplasia
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Self-citationJääskeläinen, J., Levo, A., Voutilainen, R., & Partanen, J. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.10.4271 · Cited by 149 · see citing works
“In addition to these technical difficulties in mutation detection, discrepancies in genotype-phenotype correlation may result from de novo conversions, more than one partially inactivating mutation on a single allele, or unique singlefamily mutations, whose frequency does not seem to be negligible (7, 10, 11, 23, 26).”
BackgroundMethodMutations in steroid 21-hydroxylase (CYP21)
White, P. C., Tusie-Luna, M.-T., New, M. I., & Speiser, P. W. (1994) · Human Mutation · doi:10.1002/humu.1380030408 · Cited by 129 · see citing works
<i>CYP21A2</i>mutation update: Comprehensive analysis of databases and published genetic variants
Simonetti, L., Bruque, C. D., Fernández, C. S., Benavides-Mori, B., Delea, M., Kolomenski, J. E., Espeche, L. D., Buzzalino, N. D., Nadra, A. D., & Dain, L. (2018) · Human Mutation · doi:10.1002/humu.23351 · Cited by 122 · see citing works
Analysis of steroid 21-hydroxylase gene mutations in the Spanish population
Ezquieta, B., Oliver, A., Gracía, R., & Gancedo, P. G. (1995) · Human Genetics · doi:10.1007/bf00207379 · Cited by 112 · see citing works
“The sequences selected for specificity were: the normal counterparts of the 8-bp deletion (del8bp) in exon 3 (Owerbach et al. 1990; Tusie-Luna et al. 1991; Wedell and Luthman 1993) or codons 236-239 in exon 6 that differentiate CYP21B from CYP21A by four deoxynucleotides (Owerbach et al.”
BackgroundBaumgartner-Parzer, S., Witsch-Baumgartner, M., & Hoeppner, W. (2020) · European Journal of Human Genetics · doi:10.1038/s41431-020-0653-5 · Cited by 110 · see citing works
Bachega, T. A. S. S., Billerbeck, A. E. C., Madureira, G., Marcondes, J. A. M., Longui, C. A., Leite, M. V., Arnhold, I. J. P., & Mendonca, B. B. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.12.5350 · Cited by 108 · see citing works
“(19), was used for identification of the T insertion on exon 7, P453S, G291S, I7 splice, W405X, R483P, and R4833frameshift.”
MethodHall, C. M., Jones, J. A., Meyer-Bahlburg, H. F. L., Dolezal, C., Coleman, M., Foster, P., Price, D. A., & Clayton, P. E. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030696 · Cited by 101 · see citing works
“The nucleotide positions are as described in the Human Gene Mutation Base (Cardiff, UK), and the PCR methodology is adapted from that of Wedell and Luthman (26).”
MethodNordenström, A., Thilén, A., Hagenfeldt, L., Larsson, A., & Wedell, A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.5.5651 · Cited by 2 · see citing works
“CYP21 mutation analysis was carried out using allele-specific PCR from genomic DNA prepared from venous blood samples ( 13 ).”
MethodSelf-citationMarino, R., Ramirez, P., Galeano, J., Perez Garrido, N., Rocco, C., Ciaccio, M., Warman, D. M., Guercio, G., Chaler, E., Maceiras, M., et al. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04123.x · Cited by 98 · see citing works
CONGENITAL ADRENAL HYPERPLASIA
Pang, S. (1997) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70285-1 · Cited by 94 · see citing works
Wedell, A. (1998) · Acta Paediatrica · doi:10.1080/08035259850157598 · Cited by 103 · see citing works
Self-citationBachega, T. A. S. S., Billerbeck, A. E. C., Marcondes, J. A. M., Madureira, G., Arnhold, I. J. P., & Mendonca, B. B. (2000) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2000.00995.x · Cited by 90 · see citing works
“Allele-speci®c PCR methodology described by Wedell & Luthman (1993) was used for the identi®cation of rare mutations as: Ins T, G291S, I7 splice, W405X, P453S, R483P and R483!frameshift mutations.”
MethodExtraadrenal 21-Hydroxylation by CYP2C19 and CYP3A4: Effect on 21-Hydroxylase Deficiency
Gomes, L. G., Huang, N., Agrawal, V., Mendonça, B. B., Bachega, T. A. S. S., & Miller, W. L. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1174 · Cited by 91 · see citing works
“The CYP21A2 genes of all 109 patients were previously analyzed by Southern blotting to determine large rearrangements (26), and by allele-specific PCR to determine 15 common microconversions resembling point mutations (27, 28).”
MethodHigh Incidence of Molecular Defects of the CYP21 Gene in Patients with Premature Adrenarche
Dacou‐Voutetakis, C., & Dracopoulou, M. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.5.5683 · Cited by 95 · see citing works
“Downloaded from jcem.endojournals.org by on February 2, 2010 method proposed by Wedel and Luthman was followed with slight modifications ( 13 ).”
MethodBiochemical and genetic diagnosis of 21-hydroxylase deficiency
Falhammar, H., Wedell, A., & Nordenström, A. (2015) · Endocrine · doi:10.1007/s12020-015-0731-6 · Cited by 80 · see citing works
“Several protocols are available for accurate genotyping, mostly based on CYP21A2-specific PCR, followed by sequencing [54], combined with multiplex ligation-dependent probe amplification (MLPA) or real-time PCR for quantitation.”
Self-citationHigh Fetal Testosterone and Sexually Dimorphic Cerebral Networks in Females
Ciumas, C., Hirschberg, A. L., & Savic, I. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhn160 · Cited by 76 · see citing works
“The diagnosis was based on CYP21 mutation analysis using allele-specific PCR from genomic DNA prepared from venous blood (Wedell and Luthman 1993).”
MethodWedell, A. (1998) · Acta Paediatrica · doi:10.1111/j.1651-2227.1998.tb00968.x · Cited by 73 · see citing works
“Instead, a longer control fragment, representing CYP21P, is produced (19).”
Self-citationde Carvalho, D. F., Miranda, M. C., Gomes, L. G., Madureira, G., Marcondes, J. A. M., Billerbeck, A. E. C., Rodrigues, A. S., Presti, P. F., Kuperman, H., Damiani, D., et al. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0171 · Cited by 75 · see citing works
Baumgartner-Parzer, S. M., Schulze, E., Waldhäusl, W., Pauschenwein, S., Rondot, S., Nowotny, P., Meyer, K., Frisch, H., Waldhauser, F., & Vierhapper, H. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.10.7898 · Cited by 74 · see citing works
“Together with apparent gene deletions and large gene conversions, nine pseudogene-derived mutations are responsible for approximately 90 –95% of all CAH alleles ( 11 ).”
BackgroundNishi, M. Y., Domenice, S., de Medeiros, M. A., Mendonca, B. B., & Billerbeck, A. E. C. (2002) · American Journal of Medical Genetics · doi:10.1002/ajmg.10168 · Cited by 72 · see citing works
Araújo, R. S., Mendonca, B. B., Barbosa, A. S., Lin, C. J., Marcondes, J. A. M., Billerbeck, A. E. C., & Bachega, T. A. S. S. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2163 · Cited by 70 · see citing works
“a Primers from Wedell and Luthman (26).”
MethodLajić, S., Levo, A., Nikoshkov, A., Lundberg, Y., Partanen, J., & Wedell, A. (1997) · Human Genetics · doi:10.1007/s004390050436 · Cited by 66 · see citing works
“Ten such rare mutations have been described so far, six of which are missense mutations (Helmberg et al. 1992; Wedell et al. 1992; Gunn et al. 1993; Wedell and Luthman 1993 a, b; Lajic and Wedell 1996; Levo and Partanen 1997 a). We here describe two additional missense mutations, one found in a Swedish patient origina…”
BackgroundMethodInfluentialSelf-citationKleinle, S., Lang, R., Fischer, G. F., Vierhapper, H., Waldhauser, F., Födinger, M., & Baumgartner-Parzer, S. M. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0487 · Cited by 67 · see citing works
Nordenström, A., Ahmed, S., Jones, J., Coleman, M., Price, D. A., Clayton, P. E., & Hall, C. M. (2005) · Hormone Research in Paediatrics · doi:10.1159/000082896 · Cited by 66 · see citing works
CYP21 mutations and congenital adrenal hyperplasia
Lee, H. (2001) · Clinical Genetics · doi:10.1034/j.1399-0004.2001.590501.x · Cited by 63 · see citing works
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“A mutation in the adjacent nucleotide 1784 was identified in a Swedish patient carrying the salt-wasting phenotype (Wedell and Luthman 1993b).”
BackgroundBillerbeck, A. E. C., Mendonca, B. B., Pinto, E. M., Madureira, G., Arnhold, I. J. P., & Bachega, T. A. S. S. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2001-011939 · Cited by 65 · see citing works
Molecular Genetics of 21- Hydroxylase Deficiency
Wedell, A. (2010) · Endocrine development · doi:10.1159/000321223 · Cited by 64 · see citing works
Self-citationFriães, A., Rêgo, A. T., Aragüés, J. M., Moura, L. F., Mirante, A., Mascarenhas, M. R., Kay, T. T., Lopes, L. A., Rodrigues, J. C., Guerra, S., et al. (2006) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2005.11.015 · Cited by 63 · see citing works
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“Determination of the known pseudogene-derived mutations in CYP21 (White et al. 1994) was performed using gene-specific PCR amplification followed by mutation-specific PCR (a local modification of the method described in Wedell and Luthman 1993b ), direct DNA sequencing, or PCR/RFLP.”
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“Allele-specific PCR was employed, as previously described by A. Wedell and H. Luthman ( 8 ), to identify the following molecular defects of the CYP21 gene: P30L (exon 1); I2 splice (intron 2); 8bpdE3 (exon 3); I172N (exon 4); clusterE6 (exon 6); V281L, G291S, and F3061T (exon 7); Q318stop and R356W (exon 8); and P453S…”
Synergistic Effect of Partially Inactivating Mutations in Steroid 21-Hydroxylase Deficiency
Nikoshkov, A., Lajić, S., Holst, M., Wedell, A., & Luthman, H. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.1.3678 · Cited by 64 · see citing works
“By typing for nine pseudogene-derived mutations by allelespecific PCR, approximately 95% of all mutated CYP21 alleles are detected ( 11 ).”
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Gonçalves, J., Friães, A., & Moura, L. (2007) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399407000300 · Cited by 60 · see citing works
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Self-citationEarly growth is not increased in untreated moderately severe 21‐hydroxylase deficiency
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Self-citationThe Adrenal Cortex and its Disorders
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Genetic Diseases of Steroid Metabolism
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Self-citationGunther, D. F., Bukowski, T. P., Ritzén, E. M., Wedell, A., & Wyk, J. J. V. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.10.4281 · Cited by 43 · see citing works
Self-citationA Novel Missense Mutation, GLY424SER, in Brazilian Patients with 21-Hydroxylase Deficiency
Billerbeck, A. E. C., Bachega, T. A. S. S., Frazzatto, E., Nishi, M. Y., Goldberg, A. C., Marin, M. L. C., Madureira, G., Monte, O., Arnhold, I. J. P., & Mendonca, B. B. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.8.5937 · Cited by 44 · see citing works
“This specificity was achieved by using a primer located in exon 3 that does not contain the eight-nucleotide deletion specific for the pseudogene. The primers used were P4 and P55 ( 10 ).”
BackgroundMethodInfluentialPatócs, A., Tóth, M., Barta, C., Sasvári‐Székely, M., Varga, I., Szücs, N., Jakab, C., Gláz, E., & Rácz, K. (2002) · European Journal of Endocrinology · doi:10.1530/eje.0.1470349 · Cited by 38 · see citing works
“has been proved to detect homozygous normal, homozygous mutant or heterozygous genotypes for the eight commonly occurring mutations with the exception of heterozygous deletion (28, 29 , 44), which could result in some underestimation of the occurrence of heterozygous carriers.”
BackgroundMethodLako, M., Ramsden, S., Campbell, R. D., & Strachan, T. (1999) · Journal of Medical Genetics · doi:10.1136/jmg.36.2.119 · Cited by 38 · see citing works
“Detection of CYP21 point mutations was carried out essentially as described by Wedell and Luthman.”
Fardella, C. E., Poggi, H., Pineda, P., Soto, J., Torrealba, I., Cattani, A., Oestreicher, E., & Foradori, A. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.9.5071 · Cited by 35 · see citing works
Lajić, S., & Wedell, A. (1996) · Human Genetics · doi:10.1007/s004390050186 · Cited by 32 · see citing works
“Nine such rare mutations have been reported to date (Wedell et al. 1992; Helmberg et al. 1992; Gunn et al. 1993; Wedell and Luthman 1993 a, b). In this communication, we describe two additional rare CYP21 mutations in two Swedish CAH patients.”
BackgroundSelf-citationOlney, R. C., Mougey, E. B., Wang, J., Shulman, D. I., & Sylvester, J. E. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8273 · Cited by 36 · see citing works
“Positive control DNA for the mutations was kindly provided by Dr. Anna Wedell (Karolinska Hospital, Stockholm, Sweden) (6).”
BackgroundMethodInfluentialMolecular Diagnosis of CYP21 Mutations in Congenital Adrenal Hyperplasia
Speiser, P. (2001) · American Journal of PharmacoGenomics · doi:10.2165/00129785-200101020-00003 · Cited by 33 · see citing works
“[44] This technique has similar advantages to the amplification created restriction site approach; it requires more PCR reactions but does not require restriction digests.”
MethodLau, I. F., Soardi, F. C., de Lemos‐Marini, S. H. V., Guerra‐Júnior, G., Baptista, M. T. M., & de Mello, M. P. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.12.8113 · Cited by 33 · see citing works
Silveira, E., Elnecave, R., Dos Santos, E., Moura, V, Pinto, E., Van Der Linden Nader, I., Mendonca, B., & Bachega, T. (2009) · Clinical Genetics · doi:10.1111/j.1399-0004.2009.01274.x · Cited by 31 · see citing works
“entire CYP21A2 gene, including the promoter region, was PCR amplified with specific primers, and the products were submitted to direct sequencing, as previously described (10, 15).”
MethodMinutolo, C., Nadra, A. D., Fernández, C. S., Taboas, M., Buzzalino, N. D., Casali, B., Belli, S., Charreau, E. H., Alba, L. G., & Daín, L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015899 · Cited by 31 · see citing works
Barbaro, M., Soardi, F. C., Östberg, L. J., Persson, B., de Mello, M. P., Wedell, A., & Lajić, S. (2014) · Clinical Endocrinology · doi:10.1111/cen.12526 · Cited by 31 · see citing works
Self-citationCongenital Adrenal Hyperplasia: The Molecular Basis of 21-Hydroxylase Deficiency in H-2aw18 Mice
Riepe, F. G., Tatzel, S., Sippell, W. G., Pleiss, J., & Krone, N. P. (2005) · Endocrinology · doi:10.1210/en.2004-1563 · Cited by 31 · see citing works
Classical and nonclassical 21‐hydroxylase deficiency: a molecular study of Argentine patients
Daín, L., Buzzalino, N. D., Oneto, A., Belli, S., Stivel, M., Pasqualini, T., Minutolo, C., Charreau, E. H., & Alba, L. G. (2002) · Clinical Endocrinology · doi:10.1046/j.0300-0664.2001.01419.x · Cited by 31 · see citing works
“Nevertheless, alleles-specific PCRs with both mutated and normal primers in different orientations (Wedell et al., 1994b) will be performed for those patients where the cis-trans segregation of mutations have not been yet determined (see Results).”
MethodInfluentialFalhammar, H., Thoren, M., & Hagenfeldt, K. (2008) · Journal of Endocrinological Investigation · doi:10.1007/bf03345586 · Cited by 30 · see citing works
Jaatinen, T., Ruuskanen, O., Truedsson, L., & Lokki, M. (1999) · Human Immunology · doi:10.1016/s0198-8859(99)00047-6 · Cited by 29 · see citing works
Lobato, M. N., Ordóñez-Sánchez, M. L., Tusié-Luna, M. T., & Meseguer, A. (1999) · Human Heredity · doi:10.1159/000022866 · Cited by 30 · see citing works
“These point mutations can lead to amino acid substitutions [6‐14], premature termination codons [15‐18], frameshift [6, 19] and mutations that affect RNA splicing [ 16 , 17, 19].”
BackgroundChoi, J. H., Kim, G.-H., & Yoo, H. (2016) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2016.21.1.1 · Cited by 29 · see citing works
The Adrenal Cortex and Its Disorders
Miller, W. L., Achermann, J. C., & Flück, C. E. (2008) · Elsevier eBooks · doi:10.1016/b978-141604090-3.50017-x · Cited by 28 · see citing works
Genetic disorders of steroid hormone synthesis and metabolism
New, M. I., & White, P. C. (1995) · Baillière s Clinical Endocrinology and Metabolism · doi:10.1016/s0950-351x(95)80587-7 · Cited by 27 · see citing works
Intronic polymorphisms of cytochromes P450
Ingelman‐Sundberg, M., & Sim, S. C. (2010) · Human Genomics · doi:10.1186/1479-7364-4-6-402 · Cited by 26 · see citing works
No overrepresentation of congenital adrenal hyperplasia in patients with adrenocortical tumours
Kjellman, M., Holst, M., Bäckdahl, M., Larsson, C., Farnebo, L., & Wedell, A. (1999) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1999.00655.x · Cited by 26 · see citing works
“By typing for nine pseudogene-derived mutations using allele-specific PCR, approximately 95% of all CYP21 mutations are detected (Wedell & Luthman, 1993).”
MethodSelf-citationMolecular Defects of the CYP21A2 Gene in Greek-Cypriot Patients with Congenital Adrenal Hyperplasia
Skordis, N., Kyriakou, A., Tardy, V., Ioannou, Y. S., Varvaresou, A., Dracopoulou, M., Patsalis, P. C., Shammas, C., Neocleous, V., & Phylactou, L. A. (2010) · Hormone Research in Paediatrics · doi:10.1159/000320040 · Cited by 25 · see citing works
“The patients were classified in the SW form when clinical and biochemical findings of renal salt wasting were evident (virilization of external genitalia, failure to thrive, hyponatremia, hyperkalemia, high renin (PRA) values, and 17-OHP value >75 nmol/l in the first month of their lives). Severe clinical symptoms of…”
Khan, A. H., Aban, M., Raza, J., Haq, N. U., Jabbar, A., & Moatter, T. (2011) · BMC Endocrine Disorders · doi:10.1186/1472-6823-11-5 · Cited by 25 · see citing works
“In one case neither of the fragments amplified, which may be due to homozygous gene deletion of CYP21A2 or to transfer into CYP21A2 of pseudogene sequences that include the 8 bp deletion in exon 3 [7].”
BackgroundMethodCongenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency
New, M. I., Lekarev, O., Mancenido, D., Parsa, A. A., & Yuen, T. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-416006-4.00003-x · Cited by 24 · see citing works
Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations
Skordis, N., Neocleous, V., Shammas, C., Phedonos, A., & Phylactou, L. (2014) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.145077 · Cited by 24 · see citing works
Yang, Y. (2001) · Molecular Diagnosis · doi:10.1054/modi.2001.26587 · Cited by 23 · see citing works
Falhammar, H., & Thoren, M. (2005) · Journal of Endocrinological Investigation · doi:10.1007/bf03347226 · Cited by 23 · see citing works
Giwercman, Y. L., Nordenskjöld, A., Ritzén, E. M., Nilsson, K. O., Ivarsson, S. A., Grandell, U., & Wedell, A. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.6.8518 · Cited by 22 · see citing works
“Genetic diagnosis of the CYP21 gene was performed by allele-specific PCR as described (20).”
MethodGergics, P., Patócs, A., Majnik, J., Balogh, K., Szappanos, Á., Tóth, M., & Rácz, K. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.04.004 · Cited by 22 · see citing works
Molecular pathology of 21‐hydroxylase deficiency
Strachan, T. (1994) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711358 · Cited by 20 · see citing works
Wedell, A., Xu, C. D., & Luthman, H. (1994) · Human Genetics · doi:10.1007/bf00210612 · Cited by 20 · see citing works
“This amplification was performed with the CYP21-specific P55/P4 fragment (Wedell and Luthman 1993b).”
BackgroundMethodInfluentialSelf-citationDisorders of sex development: a genetic study of patients in a multidisciplinary clinic
Laino, L., Majore, S., Preziosi, N., Grammatico, B., Bernardo, C. D., Scommegna, S., Rapone, A. M., Marrocco, G. A., Bottillo, I., & Grammatico, P. (2014) · Endocrine Connections · doi:10.1530/ec-14-0085 · Cited by 19 · see citing works
Bobba, A., Iolascon, A., Giannattasio, S., Albrizio, M., Sinisi, A. M., Prisco, F., Schettini, F., & Marra, E. (1997) · Journal of Medical Genetics · doi:10.1136/jmg.34.3.223 · Cited by 19 · see citing works
Genetic defects of the CYP21A2 gene in girls with premature adrenarche
Skordis, N., Shammas, C., Phedonos, A., Kyriakou, A., Toumba, M., Neocleous, V., & Phylactou, L. A. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0223-1 · Cited by 17 · see citing works
“The primers P1-P48 [18] were used to amplify the fragment containing the −370 bp CYP21A2 promoter, the 5′ untranslated region of the CYP21A2 gene that is mainly located in the first 167 nucleotides upstream the ATG codon and the 3′ untranslated region that is 536 nucleotides downstream the TGA stop codon of the CYP21A…”
MethodCYP21A2 intronic variants causing 21-hydroxylase deficiency
Concolino, P., Rizza, R., Costella, A., Carrozza, C., Zuppi, C., & Capoluongo, E. (2017) · Metabolism · doi:10.1016/j.metabol.2017.03.003 · Cited by 16 · see citing works
Mutations in the gene encoding 21-hydroxylase detected by solid-phase minisequencing
Ohlsson, G., & Schwartz, M. (1996) · Human Genetics · doi:10.1007/s004390050319 · Cited by 17 · see citing works
Bobba, A., Marra, E., Giannattasio, S., Iolascon, A., Monno, F., & MAIO, S. D. (1999) · Journal of Medical Genetics · doi:10.1136/jmg.36.8.648 · Cited by 17 · see citing works
Neocleous, V., Fanis, P., Phylactou, L. A., & Skordis, N. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00733 · Cited by 16 · see citing works
“For the amplification of the 5 untranslated region which is located in the first 167 nucleotides upstream of the ATG codon of the CYP21A2 gene, the primers P1-P48 (23) were used to amplify a fragment of 370 bp.”
MethodLajić, S., Nikoshkov, A., Holst, M., & Wedell, A. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0482 · Cited by 16 · see citing works
Self-citationLee, H., & Sf, C. (2001) · Journal of Endocrinology · doi:10.1677/joe.0.1710397 · Cited by 16 · see citing works
“The AG to GG mutation at the splicing acceptor site in intron 1 (Lajic & Wedell 1996) and the GT to CT mutation at the donor site in intron 7 (Wedell & Luthman 1993) both disrupt the canonical consensus sequences which are crucial for splicing processing.”
BackgroundHighsmith, W. E., Burch, L. H., Zhou, Z., Olsen, J. C., Strong, T. V., Smith, T., Friedman, K. J., Silverman, L. M., Boucher, R. C., Collins, F. S., et al. (1997) · Human Mutation · doi:10.1002/(sici)1098-1004(1997)9:4 · Cited by 89 · see citing works
Tantirukdham, N., Sahakitrungruang, T., Chaisiwamongkol, R., Pongpanich, M., Srichomthong, C., Assawapitaksakul, A., Buasong, A., Tongkobpetch, S., Yeetong, P., & Shotelersuk, V. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac187 · Cited by 14 · see citing works
Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency
Fajkusová (2010) · International Journal of Molecular Medicine · doi:10.3892/ijmm_00000504 · Cited by 15 · see citing works
Wedell, A. (1996) · Clinics in Laboratory Medicine · doi:10.1016/s0272-2712(18)30291-9 · Cited by 15 · see citing works
Self-citation
- Authors
- Wedell, A., & Luthman, H.
- Affiliations
- Karolinska University Hospital (SE)
- Corresponding author
- Luthman, Holger
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1993
- Volume
- 2
- Issue
- 5
- Pages
- 499-504
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2062953189
- Cited by
- 160
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2018: 2 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 7 · 2013: 3 · 2012: 3
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- 21-hydroxylase deficiency, CYP21, novel mutations, splice donor site mutation, nonsense mutation, allele-specific PCR, genetic diagnosis, congenital adrenal hyperplasia
- MeSH terms
- Adrenal Hyperplasia, Congenital, Alleles, Base Sequence, DNA, Female, Genotype, Humans, Molecular Sequence Data, Pseudogenes, Sodium Chloride, Steroid 21-Hydroxylase, DNA Probes, Polymerase Chain Reaction, Point Mutation
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