Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia.

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex

The Sudbury Neutrino Observatory

The Sudbury Neutrino Observatory is a second generation water Cherenkov detector designed to determine whether the currently observed solar neutrino deficit is a result of neutrino oscillations. The detector is unique in its use of D2O as a detection medium, permitting it to make a solar model-independent test of the neutrino oscillation hypothesis by comparison of the charged- and neutral-current interaction rates. In this paper the physical properties, construction, and preliminary operation of the Sudbury Neutrino Observatory are described. Data and predicted operating parameters are provided whenever possible.Comment: 58 pages, 12 figures, submitted to Nucl. Inst. Meth. Uses elsart and epsf style files. For additional information about SNO see http://www.sno.phy.queensu.ca . This version has some new reference

Measurement of the νe and total 8B solar neutrino fluxes with the Sudbury Neutrino Observatory phase-III data set

This paper details the solar neutrino analysis of the 385.17-day phase-III data set acquired by the Sudbury Neutrino Observatory (SNO). An array of 3He proportional counters was installed in the heavy-water target to measure precisely the rate of neutrino-deuteron neutral-current interactions. This technique to determine the total active 8B solar neutrino flux was largely independent of the methods employed in previous phases. The total flux of active neutrinos was measured to be 5.54-0.31+0.33(stat.)-0.34+0.36(syst.)×106 cm-2 s-1, consistent with previous measurements and standard solar models. A global analysis of solar and reactor neutrino mixing parameters yielded the best-fit values of Δm2=7.59-0.21+0.19×10 -5eV2 and θ=34.4-1.2+1.3degrees

Mechanical properties of Blair dolomite

Pressure-volume, uniaxial stress loading to failure, uniaxial strain, and acoustic velocity determinations were made on Blair dolomite at confining pressures ranging to 3.5 GPa (Pa = Paschals where 10/sup 5/ Pa = 1 bar or 0.1 GPa = 1 kbar). The bulk modulus K, rapidly rises from an initial 10.4 GPa (at atmospheric pressure) to 102.0 GPa at 1 GPa pressure. At higher pressures, K remains essentially constant (110 GPa). The maximum volume change on loading is 3.9% at 3.5 GPa; the unloading closely follows the loading path. Comparison of uninxial stress tests in compression to 0.7 GPa and extension to 2.1 GPa confining pressure demonstrates that the characteristic shear stress at failure as well as the transition from brittle fracture to ductile flow is strongly dependent upon both the value of the intermediate principal stress sigma /sub 2/ and the rate of strain. The onset of dilatancy as determined in uniaxial compression occurs at about two-thirds of the failure stress. The uniaxial strain loading path is well below the failure envelope in compression. In uniaxial stress loading (compression), Young' s modulus (E) and shear modulus ( mu ) are demonstrated to be very sensitive to both confining pressure and to the level of shear stress. For example, at pressures of 0.1 MPa to 0.5 GPa, both E and mu first increase up to shear stresses of 0.05 to 0.15 GPa and then decrease at all higher stress values. These moduli are shown to be very sensitive indicators of the onset of dilatancy. Elastic moduli as derived from acoustic velocity measurements also increase with confining pressure (to 1 GPa), with the major change occurring below 0.1 GPa. All of the observations made at nonhydrostatic conditions are consistent with the closure of preexisting cracks at low pressures and low shear stresses followed by an increasing rate of crack growth as stress is increased, even at the higher corfining pressures. However, some cracks, which would normally close with hydrostatic pre ssure, remain open under uniaxial stress loading at similar mean pressures. (auth

Mechanical properties of Nugget sandstone

The mechanical properties of Nugget sandstone have been determined from a number of independent measurements at pressures up to 30 kbar. Pressure- volume, strength, uniaxial stress, and uniaxial strain tests yield the failure surface and effective moduli as a function of stress state, i.e., mean pressure and shear stress. Acoustic velocity determinations provide the effective moduli for low-amplitude dynamic waves. At atmospheric pressure the initial effective bulk modulus in tests with applied differential stresses (~40 kbar) differs from that determined hydrostatically (23 kbar). This and a large pressure derivative of the shear modulus at low pressure are believed to be due to an abundance of cracks with low aspect ratios. The initial effective shear modulus of about 55 kbar increases rapidly with the closing of cracks. At 1 kbar confining pressure, a shear modulus of about l20 kbar is determined in both uniaxial stress and uniaxial strain experiments. The rock has an ultimate strength comparable to granite (1.2 kbar unconfined) and exhibits brittle behavior at failure to the highest mean pressure studied (14 kbar). Failure is preceded by dilatant behavior. (auth

High-pressure mechanical properties of Kayenta sandstone

Pressure-volume, uniaxial strain loading, uniaxial stress loading to failure, and ultrasoric velocity detemninations have been performed on samples of Kayenta sandstone from the site of the Mixed Company event. Hydrostatic pressure of 3 GPa produces about 23% volume compression, with 9% permanent compaction remaining upon unloading. The pressure-volume data indicate that crush-up of porosity begins between 200 and 300 MPa. In uniaxial strain loading, the sandstone loads directly to the vicinity of the failure envelope, then parallels that envelope to the highest confining pressure (480 MPa). At strain rates of about 10/sup -4//s, the loading path in uniaxial strain up to 200 MPa is coincident in pressure-volume space with the shock-loading path (at a strain rate of about 10/sup 5//s) observed on samples from the same block. The permanent compaction, after unloading under conditions of uniaxial strain from 625 MPa mean pressure, is about 3.8%. Uniaxial stress loading indicates a brittle-ductile transition between 400 and 500 MPa mean pressure. Between 100 and 500 MPa mean pressure, the slope of the failure envelope is decreased consideably with respect to that below 100 MPa and between 500 and 900 MPa. This plateau, which is not present in the failure envelope for material subjected to a 700-MPa confining pressure before the uniaxial stress test, is interpreted as being due to pore crush-up during hydrostatic loading. As confining pressure is increased from 0.1 MPa to 1 GPa, the measured compressional velocity increases from 3.0 km/s to 5.0 km/s and the shear velocity increases from 1.5 km/s to 2.4 km/s. Small decreases in compressional velocity ( approximates 5%1 between 10 and 40 MPa are attributed to local brittle failure resulting from highly localized stress concentrations within the sample under hydrostatic loading. (auth

A novel cryptic splice site mutation in <em>COL1A2</em> as a cause of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an inherited genetic disorder characterized by frequent bone fractures and reduced bone mass. Most cases of OI are caused by dominantly inherited heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2. Here we describe a five-year-old boy with typical clinical, radiological and bone ultrastructural features of OI type I. Establishing the molecular genetic cause of his condition proved difficult since clinical exome and whole exome analysis was repeatedly reported negative. Finally, manual analysis of exome data revealed a silent COL1A2 variant c.3597 T &gt; A (NM_000089.4), which we demonstrate activates a cryptic splice site. The newly generated splice acceptor in exon 50 is much more accessible than the wild-type splice-site between the junction of exon 49 and 50, and results in an in-frame deletion of 24 amino acids of the C-terminal propeptide. In vitro collagen expression studies confirmed cellular accumulation and decreased COL1A2 secretion to 45%. This is the first report of a cryptic splice site within the coding region of COL1A2. which results in abnormal splicing causing OI. The experience from this case demonstrates that routine diagnostic approaches may miss cryptic splicing mutations in causative genes due to the lack of universally applicable algorithms for splice-site prediction. In exome-negative cases, in-depth analysis of common causative genes should be conducted and trio-exome analysis is recommended

Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome.

The nail patella syndrome (NPS1) is an autosomal dominant disorder characterised by dysplasia of the finger nails and skeletal abnormalities. NPS1 has been mapped to 9q34, to a 1 cM interval between D9S315 and the adenylate kinase gene (AK1). We have mapped the breakpoints within the candidate NPS1 region in two unrelated patients with balanced translocations, One patient [46,XY,t(1;9) (q32,1;q34)] was detected during a systematic survey of old cytogenetic files in Denmark and southern Sweden. The other patient [46,XY,t(9;17) (q34,1;q25)] was reported previously D9S315 and AK1 were used to isolate YACs, from which endclones were used to isolate PACs, Two overlapping PAC clones span the 9q34 breakpoints in both patients, suggesting that NPS1 is caused by halopinsufficiency due to truncation or otherwise inactivation of a gene at or in the vicinity of the breakpoints

Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring

POGZ-related disorders (also known as White-Sutton syndrome) encompass a wide range of neurocognitive abnormalities and other accompanying anomalies. Disease severity varies widely among POGZ patients and studies investigating genotype-phenotype association are scarce. Therefore, our aim was to collect data on previously unreported POGZ patients and perform a large-scale phenotype-genotype comparison from published data. Overall, 117 POGZ patients' genotype and phenotype data were included in the analysis, including 12 novel patients. A severity scoring system was developed for the comparison. Mild and severe phenotypes were compared with the types and location of the variants and the predicted presence or absence of nonsense-mediated RNA decay (NMD). Missense variants were more often associated with mild phenotypes (p = 0.0421) and truncating variants predicted to escape NMD presented with more severe phenotypes (p < 0.0001). Within this group, variants in the prolin-rich region of the POGZ protein were associated with the most severe phenotypes (p = 0.0004). Our study suggests that gain-of-function or dominant negative effect through escaping NMD and the location of the variants in the prolin-rich domain of the protein may play an important role in the severity of manifestations of POGZ-associated neurodevelopmental disorders