F P Paranhos-Neto, L Vieira Neto, M Madeira, A B Moraes, L M C Mendonça, I C B Lima, C L R Chagas, D A Lira, J F Spitz, J A M Guimarães, M E L Duarte and M L F Farias
The role of vitamin D on bone microarchitecture and fragility is not clear.
To investigate whether vitamin D deficiency (25(OH)D <20 ng/mL) increases cortical bone loss and the severity of fractures.
Cross-sectional study of 287 elderly women with at least one prevalent low-impact fracture.
Biochemistry, X-rays to identify vertebral fractures (VFs) and to confirm non-vertebral fractures (NonVFs), and high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate bone microstructure.
Serum 25(OH)D levels were associated with body mass index (BMI: r = −0.161, P = 0.006), PTH (r = −0.165; P = 0.005), CTX (r = −0.119; P = 0.043) and vBMD at cortical bone (Dcomp: r = 0.132; P = 0.033) and entire bone (D100: r = 0.162 P = 0.009) at the distal radius, but not at the tibia. Age and PTH levels were potential confounding variables, but in the multiple linear regressions only BMI (95% CI: 0.11–4.16; P < 0.01), 25(OH)D (95% CI: −0.007 to 1.70; P = 0.05) and CTX (95% CI: −149.04 to 21.80; P < 0.01) predicted Dcomp, while BMI (95% CI: 1.13–4.18; P < 0.01) and 25(OH)D (95% CI: 0.24–1.52; P < 0.01) predicted D100. NonVFs predominated in patients with 25(OH)D <20 ng/mL (P = 0.013). Logistic regression analysis showed a decrease in the likelihood of presenting grade 2–3 VFs/NonVFs for every increase in 25(OH)D (OR = 0.962, 95% CI: 0.940–0.984; P = 0.001), BMI (OR = 0.932, 95% CI: 0.885–0.981; P = 0.007) and D100 at radius (OR = 0.994, 95% CI: 0.990–0.998; P = 0.005).
In elderly patients with prevalent fractures, vitamin D deficiency was associated with cortical bone loss and severity of fractures.
João L O Madeira, Alexander A L Jorge, Regina M Martin, Luciana R Montenegro, Marcela M Franca, Everlayny F Costalonga, Fernanda A Correa, Aline P Otto, Ivo J P Arnhold, Helayne S Freitas, Ubiratan F Machado, Berenice B Mendonca and Luciani R Carvalho
Mutations in the GH1 promoter are a rare cause of isolated growth hormone deficiency (IGHD).
To identify the molecular aetiology of a family with IGHD.
DNA sequencing, electromobility shift (EMSA) and luciferase reporter assays.
Three siblings (2M) born to consanguineous parents presented with IGHD with normal pituitary on MRI.
The GH1 proximal promoter, locus control region, five exons and four introns as well as GHRHR gene were sequenced in genomic DNA by Sanger method. DNA–protein interaction was evaluated by EMSA in nuclear extracts of GH3 pituitary cells. Dual-luciferase reporter assays were performed in cells transiently transfected with plasmids containing four different combinations of GH1 allelic variants (AV).
The patients harboured two homozygous variants (c.-185T>C and c.-223C>T) in the GH1 promoter within a highly conserved region and predicted binding sites for POU1F1/SP1 and SP1 respectively. The parents and brother were carriers and these variants were absent in 100 controls. EMSA demonstrated absent binding of GH3 nuclear extract to the c.-223C>T variant and normal binding of both POU1F1 protein and GH3 nuclear extract to the c.-185T>C variant. In contrast to GH1 promoter with AV only at c.-185, the GH1 promoter containing the AV only at c.-223 and at both positions drove significantly less expression of luciferase compared with the promoter containing either positions wild type in luciferase reporter assays.
To our knowledge, c.-223C>T is the first homozygous point mutation in the GH1 promoter that leads to short stature due to IGHD.