ABSTRACT
OBJECTIVE: To identify genetic markers associated with premature pubarche in children and hyperandrogenism in adolescent girls. DESIGN: Association study. SETTING: Academic research environment. PATIENT(S): Forty children with premature pubarche (PP), 29 adolescent girls with hyperandrogenism (HA), and 15 healthy control women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genetic variations at five loci selected because of known associations with hyperandrogenism, insulin resistance, hyperinsulinemia, or obesity. RESULT(S): Heterozygosity for CYP21 mutations was identified in 14 of 40 (35%) PP, 8 of 29 (28%) HA, and 1 of 30 (3%) controls. Heterozygosity for HSD3B2 variants was identified in 3 of 40 (7.5%) PP, 5 of 29 (17%) HA, and 0/15 controls. Among the PP, 11 of 80 (14%), 5 of 80 (6%), and 7 of 80 (9%) alleles showed the IRS-1, GRL, and ADRB3 variants, respectively. Among the HA, 5 of 58 (8.6%), 3 of 58 (5%), and 6 of 58 (10%) alleles showed the IRS-1, GRL, and ADRB3 variants, respectively. Among the control participants, variant allele frequency was 1 of 30 (3.3%) for IRS-1, 2 of 30 (6.6%) for GRL, and 2 of 30 (6.6%) for ADRB3. CONCLUSION(S): Our findings suggest that the development of PP and HA can be associated with the occurrence of multiple sequence variants at five susceptibility loci, especially steroidogenic enzyme genes. This approach offers a novel paradigm to investigate and identify the genetic factors relevant to polycystic ovary syndrome.
Subject(s)
Hyperandrogenism/genetics , Puberty, Precocious/genetics , 3-Hydroxysteroid Dehydrogenases/genetics , Adolescent , Adult , Androstenedione/blood , Body Mass Index , Child , Child, Preschool , Cytochrome P-450 Enzyme System/genetics , Female , Genetic Markers , Genetic Predisposition to Disease , Genetic Variation , Hirsutism/genetics , Humans , Hyperandrogenism/blood , Insulin Receptor Substrate Proteins , Male , Phosphoproteins/genetics , Puberty, Precocious/blood , Receptors, Adrenergic, beta-3/genetics , Receptors, Glucocorticoid/genetics , Reference Values , Steroid 21-Hydroxylase/genetics , Testosterone/bloodABSTRACT
Cryptorchidism is a common anomaly of male sexual differentiation. Two phases of testicular descent are recognized, transabdominal and inguinoscrotal. With evidence that androgens and Müllerian inhibitory hormone were not completely responsible for testicular descent, the existence of a third testicular hormone mediating testicular descent was postulated. Insulin-like 3 (INSL3) [also known as relaxin-like factor (RLF) and Leydig insulin-like protein (LEY I-L)] is a member of the insulin/relaxin hormone superfamily that is highly expressed in Leydig cells. The phenotype of transgenic mice with targeted deletion of the Insl3 gene was bilateral cryptorchidism with morphological evidence of abnormal gubernacular development. With this implicit evidence that Insl3 mediates testicular descent in mice, we performed mutation detection analysis of the coding regions of the 2 exon INSL3 gene in genomic DNA samples obtained from 145 formerly cryptorchid patients and 36 adult male controls. Single-strand conformational polymorphism analysis was used for the mutation detection studies. Two mutations, R49X and P69L, and several polymorphisms were identified. Both mutations were located in the connecting peptide region of the protein. The frequency of INSL3/RLF gene mutations as a cause of cryptorchidism is low, because only 2 of 145 (1.4%) formerly cryptorchid patients were found to have mutations.
