Tomoaki Sano

Aromatase Excess Syndrome: Identification of Cryptic Duplications and Deletions Leading to Gain of Function of CYP19A1 and Assessment of Phenotypic Determinants

CONTEXT Aromatase excess syndrome (AEXS) is a rare autosomal dominant disorder characterized by gynecomastia. Although cryptic inversions leading to abnormal fusions between CYP19A1 encoding aromatase and its neighboring genes have been identified in a few patients, the molecular basis remains largely unknown. OBJECTIVE The objective of the study was to examine the genetic causes and phenotypic determinants in AEXS. PATIENTS Eighteen affected males from six families participated in the study. RESULTS We identified three types of heterozygous genomic rearrangements, i.e. a 79,156-bp tandem duplication involving seven of 11 noncoding CYP19A1 exons 1, a 211,631-bp deletion involving exons 2-43 of DMXL2 and exons 5-10 of GLDN, and a 165,901-bp deletion involving exons 2-43 of DMXL2. The duplicated exon 1 functioned as transcription start sites, and the two types of deletions produced the same chimeric mRNA consisting of DMXL2 exon 1 and CYP19A1 coding exons. The DMXL2 exon 1 harbored a translation start codon, and the DMXL2/CYP19A1 chimeric mRNA was identified in only 2-5% of CYP19A1-positive transcripts. This was in contrast to the inversion-mediated chimeric mRNA that had no coding sequence on the fused exon 1 and accounted for greater than 80% of CYP19A1-positive transcripts. CYP19A1 was expressed in a limited number of tissues, whereas its neighboring genes involved in the chimeric mRNA formation were expressed widely. CONCLUSIONS This study provides novel mechanisms leading to gain of function of CYP19A1. Furthermore, it appears that clinical severity of AEXS is primarily determined by the tissue expression pattern of relevant genes and by the structural property of promoter-associated exons of chimeric mRNA.

Role of Counterregulatory Hormones for Glucose Metabolism in Children and Adolescents with Type 1 Diabetes

To elucidate the mechanism of insulin resistance due to insulin counterregulatory hormones (ICRHs) and evaluate ICRH secretion kinetics, ICRH concentrations were measured and correlated with blood glucose levels in 28 type 1 diabetic patients. Blood glucose was measured before bedtime. Early morning urine samples were collected the next morning before insulin injection and breakfast. Fasting blood glucose, cortisol, glucagon and HbA1c levels were measured. Growth hormone (GH), adrenaline, cortisol and C-peptide levels in morning urine samples were measured; SD scores were calculated for urine GH. The laboratory values (mean ± SD) were as follows; HbA1c of 8.1% ± 1.4%; pre-bedtime glucose of 203 ± 105 mg/dl; fasting blood glucose of 145 ± 87 mg/dl; serum cortisol of 21.6 ± 5.5 µg/dl; plasma glucagon of 98 ± 41 pg/ml; urinary GH, 27.2 ± 13.0 ng/gCr; urinary cortisol of 238 ± 197 ng/gCr; and urinary Adrenaline of 22.9 ± 21.0 ng/gCr. The mean urinary GH SD score was increased (+1.01 ± 0.70; p=0.000); the mean plasma glucagon lebel (98 ± 41 pg/ml) was not. Fasting blood glucose was positively correlated with plasma glucagon (R=0.378, p=0.0471) and negatively correlated with urinary cortisol (R=–0.476, p=0.010). Urinary adrenaline correlated positively with urinary GH (R=0.470, p=0.013) and urinary cortisol (R=0.522, p=0.004). In type 1 diabetes, GH, glucagon and cortisol hypersecretion may contribute to insulin resistance, but the mechanism remains unclear.