uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Show others and affiliations
2015 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, no 1, 37-44 p.Article in journal (Refereed) Published
Abstract [en]

BackgroundA detailed genotype-phenotype evaluation is presented by studying the enzyme activities of five rare amino acid substitutions (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile) identified in the CYP21A2 gene in patients investigated for Congenital adrenal hyperplasia (CAH). ObjectiveTo investigate whether the mutations identified in the CYP21A2 gene are disease causing and to establish a gradient for the degree of enzyme impairment to improve prediction of patient phenotype. Design and patientsThe CYP21A2 genes of seven patients investigated for CAH were sequenced and five mutations were identified. The mutant proteins were expressed in vitro in COS-1 cells, and the enzyme activities towards the two natural substrates were determined to verify the disease-causing state of the mutations. The in vitro activities of these rare mutations were also compared with the activities of four mutations known to cause nonclassic CAH (Pro30Leu, Val281Leu, Pro453Ser and Pro482Ser) in addition to an in silico structural evaluation of the novel mutants. Main outcome measureTo verify the disease-causing state of novel mutations. ResultsFive CYP21A2 mutations were identified (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile). All mutant proteins exhibited enzyme activities above 5%, and four mutations were classified as nonclassic and one as a normal variant. By comparing the investigated protein changes with four common mutations causing nonclassic CAH, a gradient for the degree of enzyme impairment could be established. Studying rare mutations in CAH increases our knowledge regarding the molecular mechanisms that render a mutation pathogenic. It also improves phenotype predictions and genetic counselling for future generations.

Place, publisher, year, edition, pages
2015. Vol. 82, no 1, 37-44 p.
National Category
Medical Genetics
URN: urn:nbn:se:uu:diva-242377DOI: 10.1111/cen.12526ISI: 000346788000007OAI: oai:DiVA.org:uu-242377DiVA: diva2:783610
Available from: 2015-01-26 Created: 2015-01-26 Last updated: 2015-01-26Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Persson, Bengt
By organisation
Computational and Systems BiologyScience for Life Laboratory, SciLifeLab
In the same journal
Clinical Endocrinology
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 540 hits
ReferencesLink to record
Permanent link

Direct link