p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency.
BACKGROUND
Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with good genotype/phenotype relationships for common mutations. To determine the severity of rare mutations is essential for genetic counseling and better understanding of the structure-function of the cytochrome P450c21.


OBJECTIVE
The p.H62L mutation was the most frequent of 60 new mutations detected in 2900 steroid 21-hydroxylase deficiency patients, either isolated or associated on the same allele with a mild mutation (p.P453S, p.P30L, or partial promoter). Because phenotypes seemed to differ between patients with isolated or associated p.H62L, a detailed phenotype description and functional studies were performed.


RESULTS
Regarding phenotype, patients with isolated p.H62L had a nonclassical form, whereas patients with the association p.H62L + mild mutation had a simple virilizing form. Functional studies showed that p.H62L reduced the conversion of the two substrates, progesterone and 17-hydroxyprogesterone, in the same way as the mild p.P453S; the association p.H62L + p.P453S decreased enzymatic activity more strongly while conserving residual activity at a level intermediate between p.P453S and p.I172N. This suggested that p.H62L was a mild mutation, whereas a synergistic effect occurred when it was associated. Analysis of p.H62L in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, the H62 being located in a domain implied in membrane anchoring.


CONCLUSIONS
According to phenotype and functional studies, p.H62L is a mild mutation, responsible for a more severe phenotype when associated with another mild mutation. These data are important for patient management and genetic counseling.
Menassa
R
R
Laboratoire d'Endocrinologie Moléculaire et Maladies Rares, Centre de Biologie et de Pathologie Est, Bron Cedex, France.
Tardy
V
V
Despert
F
F
Bouvattier-Morel
C
C
Brossier
J P
JP
Cartigny
M
M
Morel
Y
Y
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D013255:Steroid 21-Hydroxylase / Q000737:chemistry / Q000235:genetics*
D013255:Steroid 21-Hydroxylase