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CYP21 mutations in simple virilizing congenital adrenal hyperplasia

We studied the functional and structural effects of two unique missense mutations in CYP21 found in patients with simple virilizing congenital adrenal hyperplasia. The rare variants L300F and V281G were found in two girls who were each hemizygous for one of the mutations. Functional analysis after e... Full description

Journal Title: Journal of molecular medicine (Berlin Germany), 2001, Vol.79 (10), p.581-586
Main Author: LAJIC, Svetlana
Other Authors: ROBINS, Tiina , KRONE, Nils , SCHWARZ, Hans P , WEDELL, Anna
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Berlin: Springer
ID: ISSN: 0946-2716
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recordid: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_1937615
title: CYP21 mutations in simple virilizing congenital adrenal hyperplasia
format: Article
creator:
  • LAJIC, Svetlana
  • ROBINS, Tiina
  • KRONE, Nils
  • SCHWARZ, Hans P
  • WEDELL, Anna
subjects:
  • 17-alpha-Hydroxyprogesterone - metabolism
  • Adolescent
  • Adrenal Hyperplasia, Congenital - enzymology
  • Adrenal Hyperplasia, Congenital - genetics
  • Adrenogenital syndrome
  • Adult
  • Amino Acid Sequence
  • Analysis
  • Animals
  • Biological and medical sciences
  • COS Cells
  • Cytochrome P-450
  • DNA - chemistry
  • DNA - genetics
  • DNA Mutational Analysis
  • Endocrinology
  • Enzymatic activity
  • Female
  • Genetic aspects
  • Genetic disorders
  • Genetic Vectors - genetics
  • Humans
  • Hydroxylase
  • Hyperplasia
  • Investigative techniques, diagnostic techniques (general aspects)
  • Kinetics
  • Medical sciences
  • Medicin och hälsovetenskap
  • Missense mutation
  • Molecular Sequence Data
  • Mutants
  • Mutation
  • Mutation, Missense
  • Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
  • Progesterone
  • Progesterone - metabolism
  • Sequence Homology, Amino Acid
  • Steroid 21-hydroxylase
  • Steroid 21-Hydroxylase - genetics
  • Steroid 21-Hydroxylase - metabolism
  • Structure-function relationships
  • Substrate Specificity
  • Transfection
  • Virilism - enzymology
  • Virilism - genetics
ispartof: Journal of molecular medicine (Berlin, Germany), 2001, Vol.79 (10), p.581-586
description: We studied the functional and structural effects of two unique missense mutations in CYP21 found in patients with simple virilizing congenital adrenal hyperplasia. The rare variants L300F and V281G were found in two girls who were each hemizygous for one of the mutations. Functional analysis after expression in COS-1 cells revealed that the mutant enzymes had reduced enzymatic activity for conversion of both 17-hydroxyprogesterone (L300F 9.5%, V281G 3.9% of normal) and progesterone (L300F 4.4%, V281G 3.9% of normal). Both mutant enzymes had an increased degradation in mammalian COS-1 cells compared to the normal protein, although the L300F variant affected the degradation pattern to a greater extent. Our data indicate that the residue L300 is important in maintaining normal structure of the 21-hydroxylase enzyme whereas mutations affecting V281 most likely cause impaired enzyme activity by interfering with a specific function(s) of the protein.
language: eng
source:
identifier: ISSN: 0946-2716
fulltext: no_fulltext
issn:
  • 0946-2716
  • 1432-1440
url: Link


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titleCYP21 mutations in simple virilizing congenital adrenal hyperplasia
creatorLAJIC, Svetlana ; ROBINS, Tiina ; KRONE, Nils ; SCHWARZ, Hans P ; WEDELL, Anna
creatorcontribLAJIC, Svetlana ; ROBINS, Tiina ; KRONE, Nils ; SCHWARZ, Hans P ; WEDELL, Anna
descriptionWe studied the functional and structural effects of two unique missense mutations in CYP21 found in patients with simple virilizing congenital adrenal hyperplasia. The rare variants L300F and V281G were found in two girls who were each hemizygous for one of the mutations. Functional analysis after expression in COS-1 cells revealed that the mutant enzymes had reduced enzymatic activity for conversion of both 17-hydroxyprogesterone (L300F 9.5%, V281G 3.9% of normal) and progesterone (L300F 4.4%, V281G 3.9% of normal). Both mutant enzymes had an increased degradation in mammalian COS-1 cells compared to the normal protein, although the L300F variant affected the degradation pattern to a greater extent. Our data indicate that the residue L300 is important in maintaining normal structure of the 21-hydroxylase enzyme whereas mutations affecting V281 most likely cause impaired enzyme activity by interfering with a specific function(s) of the protein.
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languageeng
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subject17-alpha-Hydroxyprogesterone - metabolism ; Adolescent ; Adrenal Hyperplasia, Congenital - enzymology ; Adrenal Hyperplasia, Congenital - genetics ; Adrenogenital syndrome ; Adult ; Amino Acid Sequence ; Analysis ; Animals ; Biological and medical sciences ; COS Cells ; Cytochrome P-450 ; DNA - chemistry ; DNA - genetics ; DNA Mutational Analysis ; Endocrinology ; Enzymatic activity ; Female ; Genetic aspects ; Genetic disorders ; Genetic Vectors - genetics ; Humans ; Hydroxylase ; Hyperplasia ; Investigative techniques, diagnostic techniques (general aspects) ; Kinetics ; Medical sciences ; Medicin och hälsovetenskap ; Missense mutation ; Molecular Sequence Data ; Mutants ; Mutation ; Mutation, Missense ; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques ; Progesterone ; Progesterone - metabolism ; Sequence Homology, Amino Acid ; Steroid 21-hydroxylase ; Steroid 21-Hydroxylase - genetics ; Steroid 21-Hydroxylase - metabolism ; Structure-function relationships ; Substrate Specificity ; Transfection ; Virilism - enzymology ; Virilism - genetics
ispartofJournal of molecular medicine (Berlin, Germany), 2001, Vol.79 (10), p.581-586
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1ROBINS, Tiina
2KRONE, Nils
3SCHWARZ, Hans P
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1Journal of molecular medicine (Berlin, Germany)
addtitleJ Mol Med (Berl)
descriptionWe studied the functional and structural effects of two unique missense mutations in CYP21 found in patients with simple virilizing congenital adrenal hyperplasia. The rare variants L300F and V281G were found in two girls who were each hemizygous for one of the mutations. Functional analysis after expression in COS-1 cells revealed that the mutant enzymes had reduced enzymatic activity for conversion of both 17-hydroxyprogesterone (L300F 9.5%, V281G 3.9% of normal) and progesterone (L300F 4.4%, V281G 3.9% of normal). Both mutant enzymes had an increased degradation in mammalian COS-1 cells compared to the normal protein, although the L300F variant affected the degradation pattern to a greater extent. Our data indicate that the residue L300 is important in maintaining normal structure of the 21-hydroxylase enzyme whereas mutations affecting V281 most likely cause impaired enzyme activity by interfering with a specific function(s) of the protein.
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017-alpha-Hydroxyprogesterone - metabolism
1Adolescent
2Adrenal Hyperplasia, Congenital - enzymology
3Adrenal Hyperplasia, Congenital - genetics
4Adrenogenital syndrome
5Adult
6Amino Acid Sequence
7Analysis
8Animals
9Biological and medical sciences
10COS Cells
11Cytochrome P-450
12DNA - chemistry
13DNA - genetics
14DNA Mutational Analysis
15Endocrinology
16Enzymatic activity
17Female
18Genetic aspects
19Genetic disorders
20Genetic Vectors - genetics
21Humans
22Hydroxylase
23Hyperplasia
24Investigative techniques, diagnostic techniques (general aspects)
25Kinetics
26Medical sciences
27Medicin och hälsovetenskap
28Missense mutation
29Molecular Sequence Data
30Mutants
31Mutation
32Mutation, Missense
33Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
34Progesterone
35Progesterone - metabolism
36Sequence Homology, Amino Acid
37Steroid 21-hydroxylase
38Steroid 21-Hydroxylase - genetics
39Steroid 21-Hydroxylase - metabolism
40Structure-function relationships
41Substrate Specificity
42Transfection
43Virilism - enzymology
44Virilism - genetics
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titleCYP21 mutations in simple virilizing congenital adrenal hyperplasia
authorLAJIC, Svetlana ; ROBINS, Tiina ; KRONE, Nils ; SCHWARZ, Hans P ; WEDELL, Anna
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017-alpha-Hydroxyprogesterone - metabolism
1Adolescent
2Adrenal Hyperplasia, Congenital - enzymology
3Adrenal Hyperplasia, Congenital - genetics
4Adrenogenital syndrome
5Adult
6Amino Acid Sequence
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22Hydroxylase
23Hyperplasia
24Investigative techniques, diagnostic techniques (general aspects)
25Kinetics
26Medical sciences
27Medicin och hälsovetenskap
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29Molecular Sequence Data
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31Mutation
32Mutation, Missense
33Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
34Progesterone
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36Sequence Homology, Amino Acid
37Steroid 21-hydroxylase
38Steroid 21-Hydroxylase - genetics
39Steroid 21-Hydroxylase - metabolism
40Structure-function relationships
41Substrate Specificity
42Transfection
43Virilism - enzymology
44Virilism - genetics
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issn0946-2716
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abstractWe studied the functional and structural effects of two unique missense mutations in CYP21 found in patients with simple virilizing congenital adrenal hyperplasia. The rare variants L300F and V281G were found in two girls who were each hemizygous for one of the mutations. Functional analysis after expression in COS-1 cells revealed that the mutant enzymes had reduced enzymatic activity for conversion of both 17-hydroxyprogesterone (L300F 9.5%, V281G 3.9% of normal) and progesterone (L300F 4.4%, V281G 3.9% of normal). Both mutant enzymes had an increased degradation in mammalian COS-1 cells compared to the normal protein, although the L300F variant affected the degradation pattern to a greater extent. Our data indicate that the residue L300 is important in maintaining normal structure of the 21-hydroxylase enzyme whereas mutations affecting V281 most likely cause impaired enzyme activity by interfering with a specific function(s) of the protein.
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