TY - JOUR
T1 - Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency
AU - Speiser, Phyllis W.
AU - Dupont, Jakob
AU - Zhu, Deguang
AU - Serrat, Jorge
AU - Buegeleisen, Miriam
AU - Tusie-Luna, Maria Teresa
AU - Lesser, Martin
AU - New, Maria I.
AU - White, Perrin C.
PY - 1992
Y1 - 1992
N2 - Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A → G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172 → Asn (16%), and Val-281 → Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy.
AB - Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A → G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172 → Asn (16%), and Val-281 → Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy.
KW - Allelic variation
KW - CYP21
KW - Steroid 21-hydroxylase deficiency
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M3 - Article
C2 - 1644925
AN - SCOPUS:0026641101
SN - 0021-9738
VL - 90
SP - 584
EP - 595
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -