Table 5.
Molecular defects in the CYP19A1 gene, in vitro aromatase activity of mutants, and clinical phenotype in published male aromatase-deficient subjects.
| gene mutations | Description | Aromatase activity | Phenotype | References |
|---|---|---|---|---|
| c.[1123C>T];[1123C>T] | p.Arg375Cys in a highly conserved region. | 0.2 % of WT activity. Protein modeling studies suggest that the affected region may be important in anchoring the region of the protein proximal to the substrate access channel to the membrane. |
Continuous linear growth, delayed bone maturation, tall stature, eunuchoid body proportions Cisgender, heterosexual, modest libido. Macroorchidism Increased basal gonadotropins and testosterone. Hypertension, Obesity Dyslipidemia, Insulin Resistance Osteopenia |
(77) |
| c.[1094G>A];[1094G>A] | p.Arg365Gln | 0.4% of WT activity. | Continuous linear growth, delayed bone maturation, tall stature, eunuchoid body proportion Moderate bone pain. Genu valgum. Cisgender identity and sexual orientation. Normal libido. Infertility Microorchidism Normal basal testosterone, slightly elevated FSH and LH in the upper normal range. Overweight. Dyslipidemia Normal OGTT |
(78) |
| c.[469delC];[469delC] | p.Val158PhefsTer20 C base deletion in exon 5 causing a frame shift and a premature stop codon after 21 codons. |
Not determined (ND). However, the resultant peptide does not contain the substrate-binding pocket (I helix), the electron-accepting site and the heme-binding site. An inactive protein would be expected. |
At birth: Normal genitalia, and serum AMH levels. Normal serum basal and GnRH stimulated FSH levels at 2 months of age. At 16 years: Tall stature, delayed bone maturation. Normal virilization and testicular volume. High serum basal testosterone, and normal serum basal gonadotropin levels. Osteoporosis. |
(79, 80) |
| c.[628-3C>A];[628-3C>A] | IVS5-3C>A C to A transition at bp−3 at the splicing acceptor site in exon 6. Exon 6 is completely excised leading to a frame shift and premature stop codon 8 nucleotides downstream the end of exon 5. |
ND. The resulting peptide most likely will not be processed, but even if it were, it would not result in a functional aromatase because it lacks the substrate-binding pocket, the electron-accepting site and the heme-binding site (81) |
Continuous linear growth, tall stature, eunuchoid body proportion. Genu valgum, kyphoscoliosis, pectus carinatus. Cisgender, heterosexual, and normal libido. Normal genitalia and testicular volume Increased serum basal testosterone and FSH, normal serum LH levels. Azoospermia Obesity. Insulin resistance. Osteoporosis. |
(81) |
| c.[628G>A];[628G>A] | G to A transition in the last nucleotide in exon 5. The mutated DNA will generate an mRNA that includes the intron 5 sequence which contains an in-frame stop codon 30 bp downstream the splice junction. |
ND. A truncated and inactive protein lacking the heme-binding domain would be expected. |
Continuous linear growth, delayed bone maturation, tall stature, eunuchoid body proportions. Diffuse bone pain, genu valgum, Cisgender, heterosexual, referred normal libido Bilateral cryptorchidism (surgery unsuccesful at 6 years). Smal inguinal testes, total germ depletion (biopsy). Normal serum basal LH and testosterone, and increased FSH levels. Overweight, Dyslipidemia. Type 2 diabetes Osteoporosis. |
(82) |
| c.[380T>G];[1124G>A] | p.Met127Arg; p.Arg375His |
In vitro analysis demonstrated a reduction of aromatase activity when the two mutations were expressed separately or coupled.p.Arg375His showed aromatase activity of 7%. Aromatase activity decreased to 0% when the two mutations were coupled. |
Continuous linear growth, delayed bone maturation, tall stature. Diffuse bone pain, genu valgum. Cisgender, heterosexual, normal libido. Normal testicular volume. Normal serum LH and testosterone, increased FSH levels. Focal hypospermatogenesis on testicular biopsy. Obesity, acanthosis nigricans, hepatomegaly. Moderate dyslipidemia, Insulin resistance. Osteoporosis. |
(83) |
| c.[312_334del];[1263+1G>A] | p.Phe312LeufsTer49: 23 bp deletion in exon 4 that would be expected to cause a frame shift with a premature stop codon at nucleotide 361 in exon 4. IVS9+1G>T: point mutation in the first nucleotide of intron 9 that would lead to an aberrant splicing of the mRNA. |
A truncated and inactive protein lacking the heme-binding domain would be expected from the c.312_334del allele. | Continuous linear growth, delayed bone maturation, tall stature, eunuchoid body proportions, genu valgum. Cisgender, normal sexual orientation Normal testicular volume. Right cryptorchidism, surgery at 3 years. Mild asteno-teratozoospermia. Increased serum basal FSH with normal LH and testosterone levels. Overweight, Insulin resistance. Mild dyslipidemia Osteoporosis. |
(84) |
| c.[1124G>A];[1124G>A] | p.Arg375His Previously reported (83) |
Continuous linear growth, delayed bone maturation, tall stature, eunuchoid body proportions Bone pain, fractures. Macroorchidism Normal serum gonadotropin with increased testosterone levels. Normal sperm count. Overweight. Dyslipidemia. Normal OGTT. Hepatosteatosis. Osteoporosis. |
(85) | |
| c.[575 G>A];[575 G>A] | p.Arg192His Amino acid conserved across species and involved in substrate access and catalysis |
p.Arg192His mutant was found to have markedly reduced aromatase activity. Both the km and the Vmax were adversely affected. The catalytic efficiency of metabolizing androstenedione was reduced to 19%. Modeling of the structure of the novel p.Arg192His variant of the CYP19A1 protein revealed a crucial role of the arginine 192 residue in substrate binding as well as catalysis. | Mild hypospadias (glans), normal-length phallus, bilateral inguinal testes. Normal serum FSH, LH, testosterone, AMH, and inhibin B levels. |
(86) |
| c.[384A>G];[1494T>C] | p.Tyr81Cys; p.Leu451Pro. Both the Tyr81 and Leu451 residues were highly conserved in vertebrate aromatase orthologs and were also conserved in human aromatase paralogs. |
Three-dimensional modeling predicted that the p.Tyr81Cys and p.Leu451Pro mutations would probably result in loss of aromatase function. In-cell aromatase activity assay: p.Tyr81Cys mutant was found to have 14.3% wild-type activity, whereas the p.Leu451Pro mutant was found to have 3.1% wild-type activity. p.Tyr81Cys mutant showed lower Vmax, higher Km, and lower catalytic efficiency. p.Leu451Pro mutant had lower Vmax, Km and catalytic efficiency. |
Continuous linear growth, delayed bone maturation, tall stature, eunuchoid body proportions, genu valgum, Normal libido, Normal testicular volume Normal spermogram. Increased serum basal FSH, with normal LH and testosterone levels. Overweight, acanthosis nigricans, Dyslipidemia and severe steatohepatitis. Impaired glucose tolerance and hyperinsulinemia. Osteopenia. |
(87) |
| c.[628 G>A];[628G>A] | Previously reported (88) | Continuous linear growth, delayed bone maturation, unfused growth plate, arachnodactily. Normal libido. Normal testicular volume Normal serum FSH and LH levels with upper normal basal testosterone. Low BMI. Normal OGTT. Osteoporosis |
(89) | |
| c.[574C>T];[574C>T] | p.Arg192Cys. Residue highly conserved. | ND SIFT tool predicted this variant to affect protein function with a highly deleterious tolerance index score of 0.00. The mutation was predicted to be probably damaging with a score of 1.000 (sensitivity 0.00; specificity 1.00) using the structure based approach PolyPhen-2. |
Accelerated puberty and apparently normal pituitary gonadal function. Pubertal bone mineral accrual was incomplete leading to osteopenia. | (90) |
ND, Not determined; BMI, body mass index; OGTT, oral glucose tolerance test.