Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel KCNJ5 that result in cell depolarization and Ca2+ influx cause ~40% of these tumors1. We found five somatic mutations (four altering glycine 403, one altering isoleucine 770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 non-KCNJ5-mutant APAs. These mutations lie in S6 segments that line the channel pore. Both result in channel activation at less depolarized potentials, and glycine 403 mutations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, the sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. Remarkably, we identified de novo mutations at the identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain of function Ca2+ channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Osteogenesis imperfecta (OI) is a heritable disorder ofconnective tissue associated with fractures, osteopenia, and short stature. 01 results from mutations affecting the proal or proa2 gene of type I collagen. We describe a strain of mice with a nonlethal recessively inherited mutation (oim) that results in phenotypic and biochemical features that simulate moderate to severe human 01. Although imperfect osteogenesis has been previously observed in bovine, feline, and murine species, none of these have duplicated both the biochemical and clinical findings associated with human OI (4-7). The Mov-13 mouse, which has a transcriptional block of the proal(I) collagen gene, has provided a potential model of human 01 type II (8-13). More recently, several transgenic variants of Mov-13 and normal mice have been created as useful models of mild 01 type I or lethal OI type II (tt, 14, 15).In this report we describe a naturally occurring mouse mutation that produces phenotypic and biochemical features similar to those seen in moderate to severe human OI. We have named this mutation osteogenesis imperfecta murine (oim). Homozygous oim mice have osteopenia, fractures, and progressive skeletal deformities. Our data indicate that these mice are deficient in proa2(I) collagen because of a G deletion at nucleotide 3983 of the Cola-2 gene. This mutation results in tissue accumulation of al(I) homotrimeric collagen in the extracellular matrix. Homozygous oim mice should permit the study of type I collagen pathophysiology in a manner not possible in humans. MATERIALS AND METHODSRadiographic and Microscopic Examination. Whole-body radiographs were taken in a Faxitron x-ray machine (34 keV for 1.5 min) using Kodak OM1 film. For light microscopy, excised femurs were fixed in neutral buffered Formalin for 24 hr, decalcified in 10% (wt/vol) EDTA in 0.1 M Tris'HCl buffer, pH 6.9, for 14 days at 4°C, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.Isolation and Culture of Dermal Fibroblasts. Dermis was obtained from the back of 3-to 5-day-old homozygous oim and wild-type pups. The skin was rinsed with iodine then 70o (vol/vol) ethanol, excised, and minced to 1-to 3-mm2 pieces.Explants were grown for 2 weeks in Dulbecco's modified Eagle's medium supplemented with 10%o fetal bovine serum, streptomycin at 100 jug/ml, penicillin at 100 units/ml, and amphotericin B at 0.25 jig/ml. Cultures were assayed in the second passage.Collagen and Procollagen Analysis in Vitro. Fibroblast cultures were grown several days past visual confluence in 10-cm2 dishes. The medium was then supplemented with 150 ,uM sodium ascorbate and 24 hr later the cultures were incubated for 30 min in Dulbecco's modified Eagle's medium plus 1% dialyzed fetal bovine serum, antibiotics, 100 ,uM each nonessential amino acids but no proline, and 150 ,uM sodium ascorbate (starve medium). De novo synthesized proteins were radiolabeled for 2 hr (short-label analysis) or 24 hr (steady-state analysis) with starve medium containing 20 ,uCi (1 Ci = 37 ...

The combination of exercise plus an antiresoptive drug may be useful for protecting bone health during long-duration spaceflight.

Osteogenesis imperfecta (OI) is the most common of the inherited connective tissue disorders that primarily affect bone. However, it is a systemic disorder, as evidenced by the occurrence of ocular complications, dentinogenesis imperfecta, hearing loss, joint laxity, restrictive pulmonary disease, and short stature. The OI classification initially included four phenotypes (I-IV) involving COL1A1 and COL1A2 mutations. Three new phenotypes have been added, of which one, type VII, is the result of mutations of the cartilage-associated protein (CRTAP) gene. Investigation of recessive forms of OI particularly reported among South African blacks have revealed mutations involving both the CRTAP gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, each involved in collagen proline-3 hydroxylation. Issues related to the treatment of OI with bisphosphonates involve patient selection, evaluation of the results of treatment, and the duration of treatment. Also, questions exist regarding the difference in treatment response between children and adults with OI. Other treatment options, such as recombinant human parathyroid hormone (1-34), Rank ligand inhibitors, and stem cell technology, are being evaluated or are of future investigative interest.

Background. Adults with osteogenesis imperfecta (OI) have a high risk of fracture. Currently, few treatment options are available, and bone anabolic therapies have not been tested in clinical trials for OI treatment.Methods. 79 adults with OI were randomized to receive 20 μg recombinant human parathyroid hormone (teriparatide) or placebo for 18 months in a double-blind, placebo-controlled trial. The primary endpoint was the percent change in areal bone mineral density (aBMD) of the lumbar spine (LS), as determined by dualenergy X-ray absorptiometry. Secondary endpoints included percent change in bone remodeling markers and vertebral volumetric BMD (vBMD) by quantitative computed tomography, estimated vertebral strength by finite element analysis, and self-reported fractures.Results. Compared with the placebo group, the teriparatide group showed increased LS aBMD (6.1% ± 1.0% vs. 2.8% ± 1.0% change from baseline; P < 0.05) and total hip aBMD (2.6% ± 1.0% vs. -2.4% ± 1.0% change; P < 0.001). Vertebral vBMD and strength improved with teriparatide therapy (18% ± 6% and 15% ± 3% change, respectively), but declined with placebo (-5.0% ± 6% and -2.0% ± 3% change; P < 0.05 for both comparisons). Serum procollagen type 1 N-terminal propeptide (P1NP) and urine collagen N-telopeptide (NTx) levels increased with teriparatide therapy (135% ± 14% and 64% ± 10% change, respectively). Teriparatide-induced elevation of P1NP levels was less pronounced in severe forms of OI (type III/IV) compared with the milder form (type I). Type I OI patients exhibited robust BMD increases with teriparatide; however, there was no observed benefit for those with type III/IV OI. There was no difference in self-reported fractures between the 2 groups.Conclusions. Adults with OI, particularly those with less severe disease (type I), displayed a teriparatide-induced anabolic response, as well as increased hip and spine aBMD, vertebral vBMD, and estimated vertebral strength.Trial registration. Clinicaltrials.gov NCT00131469.

In a large cohort of osteogenesis imperfecta type V (OI type V) patients (17 individuals from 12 families), we identified the same mutation in the 5′ untranslated region (5′UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene by whole exome and Sanger sequencing (IFITM5 c.–14C > T) and provide a detailed description of their phenotype. This mutation leads to the creation of a novel start codon adding five residues to IFITM5 and was recently reported in several other OI type V families. The variability of the phenotype was quite large even within families. Whereas some patients presented with the typical calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus (HPC) formation following fractures, others had only some of the typical OI type V findings. Thirteen had calcification of interosseous membranes, 14 had radial head dislocations, 10 had HPC, 9 had long bone bowing, 11 could ambulate without assistance, and 1 had mild unilateral mixed hearing loss. The bone mineral density varied greatly, even within families. Our study thus highlights the phenotypic variability of OI type V caused by the IFITM5 mutation.

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Hearing loss was not uncommon regardless of age. Therefore, close audiological monitoring of patients with OI is recommended across the age spectrum.