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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 (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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Items 101–159 of 159
Molecular defects of the CYP21 gene in Spanish girls with isolated precocious pubarche
Potau, N., Riqué, S., Eduardo, I., Marcos, V., & Ibáñez, L. (2002) · European Journal of Endocrinology · doi:10.1530/eje.0.1470485 · Cited by 14
Variations in the 3′UTR of theCYP21A2Gene in Heterozygous Females with Hyperandrogenaemia
Neocleous, V., Fanis, P., Toumba, M., Phedonos, A., Picolos, M. K., Andreou, E., Kyriakides, T. C., Tanteles, G. A., Shammas, C., Phylactou, L. A., et al. (2017) · International Journal of Endocrinology · doi:10.1155/2017/8984365 · Cited by 14
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“Several protocols in which selective amplification of the active gene is performed before screening for different pathological mutations [10–14] have been proposed.”
BackgroundGestational Age Correlates to Genotype in Girls with CYP21 Deficiency
Gidlöf, S. B., Wedell, A., & Nordenström, A. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1369 · Cited by 13
“CYP21 mutation analysis was carried out on genomic DNA prepared from venous blood samples using allele-specific PCR and DNA sequencing (13).”
MethodSelf-citationDubey, S., Idicula‐Thomas, S., Anwaruddin, M., Chinnaraj, S., Varma, R. R., & Maitra, A. (2009) · Journal of Biomedical Science · doi:10.1186/1423-0127-16-3 · Cited by 12
“3 kb respectively using previously described primers [23].”
MethodTaboas, M., Acuña, L. I. G., Scaia, M. F., Bruque, C. D., Buzzalino, N. D., Stivel, M., Ceballos, N. R., & Daín, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0092181 · Cited by 11
“Briefly, a CYP21A2 specific fragment from exon 1 to exon 6 was amplified with primers already described [18,19].”
MethodFardella, C. E., Poggi, H., Soto, J., Torrealba, I., Cattani, A., Ugarte, F., Cortinez, A., & Foradori, A. (2000) · Journal of Endocrinological Investigation · doi:10.1007/bf03343746 · Cited by 11
Vogiatzakis, N., Kekou, K., Sofocleous, C., Kitsiou, S., Mavrou, A., Bakoula, C., & Kanavakis, E. (2007) · Molecular Biotechnology · doi:10.1007/s12033-007-0062-9 · Cited by 11
“PCR primers and conditions for the exons containing the 11 known mutations (Table 1) are as previously described [15–19].”
MethodWEI, W., & Killeen, A. A. (1998) · Molecular Diagnosis · doi:10.1016/s1084-8592(98)80036-2 · Cited by 11
Brønstad, I., Skinningsrud, B., Bratland, E., Løvås, K., Undlien, D. E., Husebye, E. S., & Wolff, A. S. B. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0432 · Cited by 11
Vogiatzakis, N., Kekou, K., Sofocleous, C., Kitsiou, S., Mavrou, A., Bakoula, C., & Kanavakis, E. (2007) · Molecular Biotechnology · doi:10.1007/s12033-007-0065-6 · Cited by 10
Root, A. W. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.5.5781 · Cited by 11
“They collected blood specimens at approximately 8–12 days of age and determined the most common CYP21 mutations in DNA extracted from peripheral leukocytes by a method that permits the analysis to be completed within hours (8).”
MethodCongenital adrenal hyperplasia
Wedell, A. (2011) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2011.02.026 · Cited by 10
Self-citationFeriotto, G., Lucci, M., Bianchi, N., Mischiati, C., & Gambari, R. (1999) · Human Mutation · doi:10.1002/(sici)1098-1004(1999)13:5 · Cited by 34
Characterization of a new splicing mutation in the steroid 21-hydroxylase gene
Рубцов, П. М., Igudin, E. L., Pichugina, M. Y., Spirin, P., Prassolov, V., & Tyulpakov, A. N. (2011) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162011060124 · Cited by 8
Livadas, S., Dracopoulou, M., Lazaropoulou, C., Papassotiriou, I., Sertedaki, A., Angelopoulos, G. N., Chrousos, G. P., & Dacou‐Voutetakis, C. (2009) · Hormone Research in Paediatrics · doi:10.1159/000249161 · Cited by 8
Katsumata, N., Shinagawa, T., Horikawa, R., & Fujikura, K. (2010) · Metabolism · doi:10.1016/j.metabol.2010.03.012 · Cited by 8
“To date, 7 intronic mutations in the CYP21A2 gene have been reported, that is, IVS2-13A/CNG [13], IVS7+1GNC [14], IVS1-2ANG [15], IVS7+2TNG [16], IVS2+1GNA [17], IVS2-2ANG [18], and IVS2+5GNA mutations [19].”
MOLECULAR ANALYSIS OF CYP21 GENE MUTATIONS CARRIED ON HLA‐B14 POSITIVE HAPLOTYPES
Dondi, E., Cuccia, M., Keller, E., Martinetti, M., Larizza, D., & Albert, E. D. (1994) · International Journal of Immunogenetics · doi:10.1111/j.1744-313x.1994.tb00204.x · Cited by 8
Analysis of DNA in Minute Volumes of Blood From Stains and Crusts
Soares-Vieira, J. A., Muñoz, D. R., Iwamura, E. S. M., Cardoso, L. D. A., & Billerbeck, A. E. C. (2001) · American Journal of Forensic Medicine & Pathology · doi:10.1097/00000433-200109000-00023 · Cited by 7
“DNA was extracted according the (modified) procedures described by Wedell and Luthman (19).”
MethodInfluentialLajić, S., Eidsmo, L., & Holst, M. (1995) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(94)00158-i · Cited by 7
Shammas, C., Byrou, S., Phelan, M. M., Toumba, M., Stylianou, C., Skordis, N., Neocleous, V., & Phylactou, L. A. (2016) · HORMONES · doi:10.14310/horm.2002.1651 · Cited by 6
Fernández, C. S., Bruque, C. D., Taboas, M., Buzzalino, N. D., Espeche, L. D., Pasqualini, T., Charreau, E. H., Alba, L. G., Ghiringhelli, P. D., & Daín, L. (2015) · Endocrine · doi:10.1007/s12020-015-0680-0 · Cited by 6
The masculinized female and investigation of abnormal sexual development
Hughes, I. A. (1998) · Baillière s Clinical Endocrinology and Metabolism · doi:10.1016/s0950-351x(98)80546-6 · Cited by 6
21-Hydroxylase deficiency in Brazil
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. (2000) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2000001000011 · Cited by 6
Khan, A. H., Nasir, M. I., & Moatter, T. (2002) · PubMed · Cited by 6
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Evgrafov, O. V., Polyakov, A. V., Dzenis, I. G., & Baharev, V. A. (1995) · Human Mutation · doi:10.1002/humu.1380050206 · Cited by 6
Sugiyama, Y., Mizuno, H., Hayashi, Y., Imamine, H., Ito, T., Kato, I., Yamamoto-Tomita, M., Aoyama, M., Asai, K., & Togari, H. (2008) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.215.341 · Cited by 5
“In addition to these four groups of mutations, five mutations that have, as yet, only been found in one patient or in one pair of siblings were placed in Group D (Wedell et al. 1992; Wedell and Luthman 1993a; Wedell and Luthman 1993b).”
BackgroundUnusual phenotype of congenital adrenal hyperplasia (CAH) with a novel mutation of the CYP21A2 gene
Raisingani, M. G., Contreras, M. F., Prasad, K., Pappas, J., Kluge, M. L., Shah, B. C., & DAVID, R. R. (2016) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2015-0457 · Cited by 5
“been associated with salt wasting CAH [3, 4].”
BackgroundIncidence of Classical 21-Hydroxylase Deficiency and Distribution of CYP21A2 Mutations in Estonia
Liivak, K., Tobi, S., Schlecht, H., & Tillmann, V. (2008) · Hormone Research in Paediatrics · doi:10.1159/000113023 · Cited by 5
“In particular, variations have been seen in patients with the intron-2 splice mutation (g.655A/C>G) (usually characteristic for the SW form) and with p.Ile172Asn (mostly found in patients with the SV form) mutations.The aims of this study were to determine the overall incidence of classical forms of 21-OHD in Estonia…”
Prenatal Diagnosis of Steroid 21-Hydroxylase Deficiency by Allele-Specific Amplification
Theodoropoulou, M., Barta, C., Szöke, M., Guttman, A., Staub, M., Niederland, T., Sólyom, J., Fekete, G., & Sasvári‐Székely, M. (2001) · Fetal Diagnosis and Therapy · doi:10.1159/000053918 · Cited by 5
Characterization of Gene Rearrangements and Gene Conversion Events in the 21-Hydroxylase Gene
Ramsden, S., & Sinnott, P. J. (2003) · Humana Press eBooks · doi:10.1385/0-89603-346-5:121 · Cited by 5
“A strategy has been described based on the use of sequence-specific PCR or ARMS (10).”
MethodYang, Y.-P., Corley, N., & Garcia‐Heras, J. (2001) · Molecular Diagnosis · doi:10.1007/bf03262053 · Cited by 4
Sanctis, V. D., Clemente, S., Gallotta, M. C., Filati, G., Fiscina, B., Marsciani, A., PIACENTINI, G. L., Timoncini, G., Reggiani, L., Zucchini, A., et al. (2012) · PubMed · Cited by 3
Genetic Analysis of Two Japanese Patients with Non-classical 21-Hydroxylase Deficiency
Imamine, R., Arima, H., Kusakabe, M., Umeda, H., Sato, I., Homma, K., Usui, T., & Oiso, Y. (2009) · Internal Medicine · doi:10.2169/internalmedicine.48.1894 · Cited by 3
“Mutations which have been implicated to cause 21OHD (deletion/conversion, 8 bp-del, L 307+T, Q318X, R356W, E6 cluster, IVS2-13 A/C>G, I172 N, P30L, V281L) were examined by either polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, allele specific PCR or nested PCR according to the r…”
MethodCongenital adrenal hyperplasia owing to 21-hydroxylase deficiency
New, M. I., Lekarev, O., Jacob, M., Macdonald, A., Parsa, A. A., & Yuen, T. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821424-4.00031-9 · Cited by 4
Lee, Y., Park, E., Kang, S., Kim, H., Lee, J. Y., & Lee, J. (2000) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2000.01090.x · Cited by 3
“Most of these are gene conversions in which one or more of the several mutations that inactivate CYP21P are instead found in CYP21 (Higashi et al., 1988; Wedell & Luthman, 1993a, b).”
BackgroundGrischuk, Y. V., Рубцов, П. М., & Beljelarskaya, S. N. (2007) · Molecular Biology · doi:10.1134/s0026893307010098 · Cited by 3
Miranda, M. C. D., Oliveira, A. C. M. D., Soares, G. J., Batatinha, J. A. P., Latronico, A. C., Mendonca, B. B., & Bachega, T. A. S. S. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1770274 · Cited by 2
“Allele-speci fi c PCR (AS-PCR), the most widely adopted molecular assay for targeted detection of the frequent CYP21A2 variants, was later described by Wedell and Luthman in 1993 (59).”
Use of nonradioactive labeling to detect large gene rearrangements in 21-hydroxylase deficiency
Cukier, P., Bachega, T. A. S. S., Mendonça, B. B., & Billerbeck, A. E. C. (2004) · Revista do Hospital das Clínicas · doi:10.1590/s0041-87812004000600010 · Cited by 1
Schernthaner-Reiter, M. H., Riedl, S., Obermayer-Pietsch, B. M., Krebs, M., Vila, G., Kleinle, S., Esterbauer, H., & Baumgartner-Parzer, S. M. (2025) · European Journal of Endocrinology · doi:10.1093/ejendo/lvaf217 · Cited by 1
Zargar, M. H., & Pandith, A. A. (2016) · Journal of Molecular and Genetic Medicine · doi:10.4172/1747-0862.1000205 · Cited by 1
“Keeping this in view, we conducted a preliminary CYP21 gene analysis in a group of patients suspected with CAH for two common mutations splice mutation in intron 2 is a frequent mutation, in which an A or C at 659 and 8bp deletion in exon 3 by ARMS PCR that can discriminate between mutation and wild type sequences, wh…”
MethodMolecular Genetics of Congenital Adrenal Hyperplasia
Parajes, S., & Krone, N. P. (2012) · Wiley eBooks · doi:10.1002/9780470015902.a0023590 · Cited by 1
Menassa, R. (2009) · theses.fr (ABES) · doi:10.70675/b3e39fd0z238az4865z8447z7bdf24b846fb · Cited by 1
Functional and structural studies on CYP21 mutants in congenital adrenal hyperplasia
Robins, T. (2005) · Figshare · Cited by 1
Silveira, E. L. (2008) · Americanae (AECID Library) · Cited by 1
21-Hydroxylase Deficiency Defects and Their Phenotype
Acerini, C. L., & Hughes, I. A. (2000) · KARGER eBooks · doi:10.1159/000060838 · Cited by 1
Genetic Studies of the Human Complement C4 Region in MHC Class III
Jaatinen, T. (2002) · Työväentutkimus Vuosikirja · Cited by 1
The Adrenal Cortex and its Disorders
Miller, W. L. (2005) · Clinical Pediatric Endocrinology · doi:10.1002/9780470987117.ch15 · Cited by 2
Gomes, L. G. (2009) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.5.2009.tde-09122009-152831
Chagay, N. B., Fadeev, V. V., Prokof'ev, S. A., Ivanova, O. N., Смирнова, Н. Б., Атаманова, Т. М., & Тишина, Ю. В. (2013) · Problems of Endocrinology · doi:10.14341/probl201359234-39
Mathur, R., & Kabra, M. (2000) · The Indian Journal of Pediatrics · doi:10.1007/bf02726225
Rothberg, P. G., Baker, D. W., & BRADLEY, J. F. (1998) · Genetic Testing · doi:10.1089/gte.1998.2.343
“The first round of PCR was used to generate a gene-specific product that was then used as template in a second round of individual allele-specific reactions (Wedell and Luthman, 1993; Wilson et al, 1995; Carrera et al, 1997).”
The assessment of the type 2 diabete risk in patients with the hyperandrogenism
Chagay, N. B., Gevorkyan, M. A., & Бакулина, Е. Г. (2015) · Russian Journal of Human Reproduction · doi:10.17116/repro201521343-50
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Test with 5 mcg ACTH for Diagnosis of Non-classic Congenital Adrenal Hyperplasia
Chagay, N. B., & Fadeyev, V. V. (2016) · Journal of Steroids & Hormonal Science · doi:10.4172/2157-7536.1000181
“Molecular genetic analysis (MGA) for most prevalent CYP21 mutations was performed using allele specific polymerase chain reaction [3].”
MethodVu, C. D., Ta, T. V., Nguyen, N., Nguyen, H.-H., Nguyen, T. K. L., Tran, T. H., & Trần, V. K. (2018) · Advances in experimental medicine and biology · doi:10.1007/5584_2018_300
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Current Aspects of Genetic Diagnosis of 21-Hydroxylase Insufficiency
Osinovskaya, N. S., Nasykhova, Y. A., Yarmolinskaya, M. I., Glavnova, O. B., & Glotov, A. S. (2021) · Doctor Ru · doi:10.31550/1727-2378-2021-20-6-73-79
Metadata
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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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