Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue. Only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. We report a novel mutation in the CYP19 gene in a sister and brother. The 28-yr-old XX proband, followed since infancy, exhibited the cardinal features of the aromatase deficiency syndrome as recently defined. She had nonadrenal female pseudohermaphrodism at birth and underwent repair of the external genitalia, including a clitorectomy. Her adult height is 177.6 cm (+2.5 SD). Her only sibling, and XY male, was studied at 24 yr of age. During both pregnancies, the mother exhibited signs of progressive virilization that regressed postpartum. The height of the brother was 204 cm (+3.7 SD) with eunuchoid skeletal proportions, and the weight was 135.1 kg (+2.1 SD). He was sexually fully mature and had macroorchidism. The bone age was 14 yr at a chronological age of 24 3/12 yr. Bone mineral densitometric indexes of the lumbar spine (cancellous bone) and distal radius (cortical bone) were consistent with osteoporosis; the distal radius was -4.7 SD below the mean value for age- and sex-matched normal men; indexes of bone turnover were increased. Analysis of genomic DNA in transformed lymphoblasts from both the sister and brother indicated a homozygous single base change at base pair 1123 (C{r_arrow}T) in exon IX of the CYP19 gene, a highly conserved region, that results in a cysteine instead of an arginine at position 375 (R375C). The parents are obligate heterozygotes in this consanguineous pedigree. Expression of the mutant complementary DNA showed that the R375C mutation had 0.2% the aromatase activity of the wild-type enzyme. 44 refs., 7 figs., 4 tabs.
- OSTI ID:
- 391044
- Journal Information:
- Journal of Clinical Endocrinology and Metabolism, Vol. 80, Issue 12; Other Information: PBD: Dec 1995
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
GENES
GENE MUTATIONS
TISSUE DISTRIBUTION
DNA SEQUENCING
STRUCTURE-ACTIVITY RELATIONSHIPS
ENZYMES
ENZYME ACTIVITY
PATIENTS
HEREDITARY DISEASES
PHENOTYPE
METABOLIC DISEASES
OSTEOPOROSIS
GENETICS
ESTROGENS
GENE REGULATION
LIPOPROTEINS
NUCLEOTIDES
EXONS
AMINO ACIDS
GENE AMPLIFICATION
ELECTROPHORESIS