Two novel mutations in the thyroglobulin gene as cause of congenital hypothyroidism: identification a cryptic donor splice site in the exon 19.

Thyroglobulin (TG) is a homodimeric glycoprotein synthesized by the thyroid gland. To date, 52 mutations of the TG gene have been identified in humans. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report a French patient with congenital hypothyroidism, mild enlarged thyroid gland and low levels of serum TG. Sequencing of DNA, genotyping, expression of chimeric minigenes as well as bioinformatics analysis were performed. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the paternal mutation consists of a c.3788-3789insT or c.3788dupT, whereas the maternal mutation consists of g.IVS19+3_+4delAT. Minigene analysis of the g.IVS19+3_+4delAT mutant showed that the exon 19 is skipped during pre-mRNA splicing or partially included by use of cryptic 5' splice site located to 100 nucleotides downstream of the wild type exon-intron junction. The c.3788-3789insT mutation results in a putative truncated protein of 1245 amino acids, whereas g.IVS19+3_4delAT mutation originates two putative truncated proteins of 1330 and 1349 amino acids. In conclusion, we show that the g.IVS19+3_+4delAT mutation promotes the activation of a cryptic donor splice site in the exon 19 of the TG gene. These results open up new perspectives in the knowledge of the mechanism of splicing for the TG pre-mRNA.

Truncal distribution of fat mass, metabolic profile and hypothalamic-pituitary adrenal axis activity in prepubertal obese children.

OBJECTIVE: To investigate whether truncal distribution of fat mass (TDFM) is associated with variations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in prepubertal obese children. STUDY DESIGN: TDFM, assessed with dual energy X-ray absorptiometry and a comprehensive set of measures of HPA axis activity and reactivity have been studied in 45 prepubertal obese children aged 6 to 11 years (girls) and 6 to 13 years (boys). RESULTS: After adjustment for whole body fat mass (%) (WBFM), TDFM correlated positively with insulin (r = 0.50, 95% CI [0.23; 0.70]) and homeostasis model assessment of insulin resistance (r = 0.52, 95% CI [0.25; 0.71]). When adjusted for WBFM, TDFM correlated positively with morning plasma cortisol (r = 0.38, 95% CI [0.15; 0.64]) in the total population. TDFM correlated negatively with the rise of salivary cortisol after a standard meal (r = -0.43, 95% CI [-0.71; -0.02]), obviously in girls. When adjusted for WBFM and TDFM, morning plasma cortisol correlated positively with total cholesterol (r = 0.41, 95% CI [0.11; 0.65]) and triglyceride (r = 0.44, 95% CI [0.14; 0.67]). The rise of salivary cortisol after a standard meal was negatively (r = -0.56, 95% CI [-0.85; -0.01]) and positively (r = 0.74, 95% CI [0.16; 0.94]) correlated with homeostasis model assessment of insulin resistance in boys and girls, respectively. CONCLUSIONS: Association exists in prepubertal obese children between TDFM and markers of HPA axis activity. These data suggest that HPA axis could be involved early in life in obesity associated with pejorative metabolic profile.