A novel missense activating mutation in the extracellular calcium-sensing receptor (CaSR) is reported in this work. It was identified in three related subjects with the phenotypic features of autosomal dominant hypocalcemia (ADH). The proband, a 27-year-old woman, diagnosed as having hypoparathyroidism at 7 years of age and a history of seizures, showed the highest penetrance of the mutation. The remaining two affected members presented asymptomatic chronic hypocalcemia despite severe hypoparathyroidism associated with high levels of serum phosphate and calcium urinary excretion. The missense mutation (Glu(604)Lys) affected an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular amino-terminal domain, which seems to be required for the coupling of ligand binding to the activation of intracellular signaling pathways. This genetic change cosegregated with hypocalcemia in all the individuals where the mutation was found. As parathyroid hormone (PTH) secretion is the regulatory target of the CaSR, polymorphism analysis of the PTH gene was carried out. PTH polymorphisms were analyzed in the kindred studied. Affected members for the Glu(604)Lys CaSR mutation which also carried the uncommon PTH alleles showed higher penetrance of the mutation, with more severe autosomal dominant hypocalcemia. These results suggested that the PTH gene could act as a modifier locus of ADH, affecting the penetrance of the activating CaSR mutation described.
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D Alvarez-Hernandez, I Santamaria, M Rodriguez-Garcia, P Iglesias, R Delgado-Lillo, and JB Cannata-Andia
T J Schoen, K Mazuruk, R J Waldbillig, J Potts, D C Beebe, G J Chader, and I R Rodriguez
We have isolated and characterized a cDNA for IGF-binding protein-2 (IGFBP-2) and its gene from the chick embryo. Using primers from a conserved region of the mammalian IGFBP-2 sequence, a cDNA clone (1·6 kb) was isolated from an embryonic day-18 chick retina cDNA library. Although the clone was truncated at the 5′ end, the complete coding sequence was obtained from 5′ rapid amplification of cDNA ends and genomic sequencing. The open reading frame encoded a 311 amino acid precursor protein which contains a putative 36 residue signal peptide. The mature 275 amino acid protein had a predicted M r of 33 500 and exhibited 71, 68, 68 and 66% identity to rat, bovine, ovine and human IGFBP-2 cDNA respectively, with conservation of all 18 cysteines. The cDNA contained an RGD peptide but lacked a putative ATP-binding motif. A single transcript of approximately 2·3 kb was present in embryonic day-15 eye, brain, skeletal muscle, heart and intestine, but was virtually absent from embryonic day-15 liver. The chicken IGFBP-2 gene spanned approximately 38 kb, consisted of four exons, and was similarly organized to that of the rat and human. Southern blot analysis of chicken genomic DNA suggested that it is encoded by a single gene. The sequence information from the avian IGFBP-2 should be of value in examining the role of IGFBP-2 in vertebrate development.
M Rodríguez-Sanz, N García-Giralt, D Prieto-Alhambra, S Servitja, S Balcells, R Pecorelli, A Díez-Pérez, D Grinberg, I Tusquets, and X Nogués
Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona–Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P<0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss.