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Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. The phenotype is highly variable, with ‘modifiers’ being discussed as potential determinants. Mismatch repair deficiency was shown to cause NF1 mutations, but constitutional mutation of mismatch repair genes was identified only once in a NF1 patient. We aimed to analyze whether DNA methylation of mismatch repair gene promoters, known to lead to transcriptional silencing, is associated with increased tumor load in NF1 defined by the number of cutaneous neurofibromas. Leukocyte DNA of 79 controls and 79 NF1 patients was investigated for methylation of mismatch repair genes MLH1, MSH2, MSH6, and PMS2 by methylation-specific PCR and pyrosequencing. MLH1, MSH6, and PMS2 promoters were not methylated. By contrast, we found promoter methylation of MSH2 with a higher rate of methylation in NF1 patients compared with controls. Furthermore, when comparing NF1 patients with a low vs those with a high number of cutaneous neurofibromas, MSH2 promoter methylation was significantly different. In patients with a high tumor burden, methylation of two (out of six) CpGs was enhanced. This finding was not confounded by age. In conclusion, enhanced methylation involving transcription start points of mismatch repair genes, such as MSH2 in NF1, has not been described so far. Methylation-induced variability of MSH2 gene expression may lead to variable mismatch repair capacity. Our results may point toward a role of MSH2 as a modifier for NF1, although the amount of DNA methylation and subsequent gene expression in other cell types of NF1 patients needs to be elucidated. [ABSTRACT FROM AUTHOR]

Abstract: A simple k–ε turbulence closure is introduced which has no stability functions but instead a Richardson number-dependent turbulent Prandtl number. Its free parameters are determined in a comparison with microstructure observations from a stratified and sheared tidal estuary and laboratory measurements. The closure is able to simulate observed turbulent dissipation rates (ε) and turbulent length scales (l th) in regions of strong mean shear and small gradient Richardson number (R g) to within factors of 2–3. It fails in regions of small shear and large R g, presumably because of the dominance of internal wave-driven mixing. Additional simulations with a k–ε closure with stability functions taken from Canuto et al. [Canuto, V.M., Howard, A., Cheng, Y., Dubovikov, M.S., 2001. Ocean turbulence I: one-point closure model. Momentum and heat vertical diffusivities. J. Phys. Oceanogr. 31, 1413–1426] and with the closure of Baumert and Peters [Baumert, H., Peters, H., 2004. Turbulence closure, steady state, and collapse into waves. J. Phys. Oceanogr. 34, 505–512] show poor performance. Establishing a valid 1:1 comparison of simulated and observed ε and l th requires nudging the model velocity and density toward observed values because free model integrations quickly diverge from the observations. Steady state gradient Richardson numbers are constrained to a range of 0.18–0.25, while flux Richardson numbers are constrained to the range of 0.1–0.22. The closure output is rather insensitive to such parameter variations. The simulations are sensitive, however, to the treatment of the observed velocity and density used to nudge the model. Good closure performance requires averaging the measured tidal flow over about an hour, a time scale for which conventional numerical models of estuarine circulations should be able to match observed shears. In the closure simulations the TKE balance stays close to a production–dissipation balance. The time rate of change and vertical diffusion of TKE are small, of the same order of magnitude, and vary in magnitude relative to each other systematically across the water column. [Copyright &y& Elsevier]

Turbulence in the Red Sea outflow plume in the western Gulf of Aden was observed with an upward-looking, five-beam, 600-kHz acoustic Doppler current profiler (ADCP). The “Bottom Lander” ADCP was deployed on the seafloor in two narrow, topographically confined outflow channels south of Bab el Mandeb for periods of 18–40 h at three locations at 376-, 496-, and 772-m depths. Two deployments were taken during the winter season of maximum outflow from the Red Sea and two in the summer season of minimum outflow. These short-term observations exhibit red velocity spectra with high-frequency fluctuations of typically a few centimeters per second RMS velocity during strong plume flow as well as strong subtidal variations. In one winter season event, the plume flow was reduced by a factor of 4 over an 18-h time span. In variance-preserving form, velocity spectra show a separation at frequencies of 0.3–3 cycles per hour between low-frequency and high-frequency signals. The latter show significant coherence between horizontal and vertical velocity components; hence they carried turbulent stress. Based on a comparison with velocity spectra from atmospheric mixed-layer observations, the authors argue that large variance at frequencies of the order of 1 cph was possibly associated with bottom-generated, upward-propagating internal waves. One coherent feature that matched such waves was observed directly. Higher frequencies correspond to turbulent motions of energy-carrying scales. The turbulent Reynolds stress at heights above the bottom between 4 and 30–40 m was computed for most of the ADCP observations. Near the bottom, the streamwise turbulent stress and the streamwise velocity followed a quadratic drag law with drag coefficients ranging from 0.002 to 0.008. There was also significant spanwise stress, hinting at the three-dimensional nature of the boundary layer flow. The time–height variations of the stress and its spectrum proved to be complex, one of its most striking features being angles of up to ∼40° between the direction of the stress and that of the low-frequency flow. The turbulent shear production and eddy viscosity were also examined. On the technical side, the paper discusses the role of the fifth, center-beam velocity measurements in correcting for instrument tilt along with the effect of beam spreading in the 30° Janus configuration of the “regular” four ADCP beams. Instrumental noise and detection limits for the stress are also established. [ABSTRACT FROM AUTHOR]

When the salty and heavy water of the Red Sea exits from the Strait of Bab el Mandeb, it continues downslope into the Gulf of Aden mainly along two channels. The 130-km-long “Northern Channel” (NC) is topographically confined and is typically only 5 km wide. In it, the Red Sea plume shows unanticipated patterns of vertical structure, turbulent mixing, and entrainment. Above the seafloor a 25–120-m-thick weakly stratified layer shows little dilution along the channel. Hence this bottom layer undergoes only weak entrainment. In contrast, a 35–285-m-thick interfacial layer shows stronger entrainment and is shown in a companion paper to undergo vigorous turbulent mixing. It is thus the interface that exhibits the bulk of entrainment of the Red Sea plume in the NC. The interfacial layer also carries most of the overall plume transport, increasingly so with downstream distance. The “Southern Channel” (SC) is wider than the NC and is accessed from the latter by a sill about 33 m above the floor of the NC. Entrainment into the bottom layer of the SC is diagnosed to be strong near the entry into the SC such that the near-bottom density and salinity are smaller in the SC than in the NC at the same distance from Bab el Mandeb. In comparison with winter conditions, the authors encountered weaker outflow with shallower equilibration depths during the summer cruise. Bulk Froude numbers computed for the whole plume varied within the range 0.2–1. Local maxima occurred in relatively steep channel sections and coincided with locations of significant entrainment. [ABSTRACT FROM AUTHOR]

South of the Strait of Bab el Mandeb, saline Red Sea Water flows downslope into the Gulf of Aden mainly along the narrow 130-km-long “Northern Channel” (NC) and the shorter and wider “Southern Channel” (SC). In the NC, the Red Sea plume simultaneously exhibited weak entrainment into a 35–120-m-thick, weakly stratified bottom layer while a 35–285-m-thick interfacial layer above showed signs of vigorous mixing, overturns up to 30 m thick, and extensive zones of gradient Richardson numbers below 1/4. Turbulent overturning scales, or Thorpe scales, are extracted from regular CTD profiles and equated to Ozmidov scales. On this basis, interfacial mixing is quantified in terms of estimated turbulent dissipation rates, vertical turbulent salt flux, and interfacial stress. Even though these estimates are subject to significant uncertainty, they demonstrate the intensity of mixing during strong winter outflow in terms of eddy diffusivities Kρ on the order of 10-2 m2 s-1. The large Kρ occur in strong stratification such that vertical turbulent salt fluxes are also large. Along the NC, relative maxima of Kρ correspond to maxima in the bulk Froude number. Direct short-term measurements of the Reynolds stress just above the seafloor at two locations, one in the NC and one in the SC, allow comparisons of the bottom stress τb with the interfacial turbulent stress τi. The ratio τi/τb shows large scatter in a small sample, with maximum values on the order of 1. Anoutlines procedures of making and reducing lowered acoustic Doppler current profiler measurements optimized for observing descending plumes. [ABSTRACT FROM AUTHOR]

Presents a simple, two-equation turbulence closure. Extra energy sink in the turbulent kinetic energy equation; Transfer of energy from turbulent kinetic energy to internal waves and other nonturbulent motions; Turbulent time scale; Turbulent dissipation rate; Buoyancy period; Onset of the collapse of turbulence into nonturbulence.

Spatial variations of vertical turbulent mixing along a stretch of the Hudson River estuary are examined with focus on the vicinity of a “hydraulic control point” at the George Washington Bridge at which the cross section narrows and the thalweg takes a bend. Richardson numbers are lowered and mixing is enhanced downstream of this “modest” morphological feature, qualitatively following predictions based on hydraulic theory by Chant and Wilson. The enhancement in the viscous dissipation rate ℇ is only a modest factor of 2–3, however, extending over 2 km along the river. Upon averaging over tidal and fortnightly cycles and multiple cruises, streamwise variations of ℇ along the probed 15-km stretch of the estuary are surprisingly small, given that individual depth averages of ℇ across the halocline vary by over three orders of magnitude. The principal result is that the observed part of the Hudson River showed strong broadly distributed mixing everywhere, with little local concentration. [ABSTRACT FROM AUTHOR]

ABSTRACT Turbulent mixing in the water column was observed with a microstructure profiler in the Hudson River estuary during two cruises in summer and fall 1995. The focus is on the estimation of turbulent salt flux and turbulent stress from measured viscous dissipation rates (e), and on the tidal and fortnightly variability of these fluxes. In estimating eddy viscosity (K[sub m]) and eddy diffusivity (K[sub p]), the authors follow measurement/modeling techniques of Busch and Osborn, while prescribing a variable flux Richardson number (R[sub j]) dependent upon the gradient Richardson number (Ri). It is argued that a steady-state production-dissipation balance holds in the turbulent kinetic energy budget. All turbulence characteristics varied strongly over semidiurnal tidal cycles and over the fortnightly cycle. Subject to complications arising from nontidal flows, the "strongest" mixing occurred during flood on neap tides, and during ebb on spring tides. In the lower part of the water column during floods and spring ebb K[sub m] and K[sub p] reached maxima of 1-5 (x 10[sup -2] m[sup 2] s[sup -1]) and decreased roughly exponentially with increasing height by 1-3 decades. The smallest eddy coefficients occurred in the halocline during neap tide with K[sub m] Is equivalent to 10[sup 4] m[sup 2] s[sup -1] and K[sub p] Is approximately equal to 10[sup -5] m[sup 2] s[sup -1]. Mostly, the internal turbulent stress (tau[sub y]) was close to 0 in the upper third of the water column and approached the bottom shear stress with decreasing height. Neap ebb had small |tau[sub y]| even close to... [ABSTRACT FROM AUTHOR]

A correction to the article "Differential MSH2 Promoter Methylation in blood Cells of Neurofibromatosis type 1 (NF1) Ptients," that was published in the 2010 issue is presented.

A correction to the article about incorrect equation by Hartmut Peters and William E. Johns is presented.

The article informs that the author claims of a better fit to laboratory data of turbulent length scales than that found in BPO4. It can be achieved either with a traditional model or with a modification of the BPO4 closure, and he finally argues that there is no need for BPO4's explicit term of energy transfer from turbulence to internal waves. The notation herein is that of K05 and BPO4 and needs no specific definitions. BPO4 deliberately refrained from tuning and optimizing parameters. This closure is not tunable; its body and its parameter values form a unity.

Abstract: The overflows of cold, heavy waters from the Nordic Seas across the Greenland–Iceland–Scotland Ridges are simulated using the Hybrid Coordinate Model in a North Atlantic configuration. Results at three different horizontal model resolutions are compared to each other, to recent hydrographic sections and moored observations. Simulations in the finest grid employed, 1/12° resolution, show realistic overflow pathways, reasonable overflow and Deep Western Boundary Current mean velocities and transports, and overall reasonable North Atlantic three-dimensional temperature and salinity fields, namely the Atlantic Meridional Overturning Circulation (AMOC). In contrast, simulations at coarser grids of 1/3° and 1° resolution exhibit a range of significant problems owing to unresolved, dynamically vital features in the seafloor topography. This lack of resolution, for example of the Faroe Bank Channel, leads to unrealistic overflow pathways between Iceland and Scotland in the 1/3° and 1° cases. Accordingly, overflow mass transports are also unrealistic in this area. In the Denmark Strait Overflow the underlying topographical scales are larger, and pathways are reasonable even at coarse resolution. However, overflow speeds are too small in the 1/3° and 1° cases. Underestimated velocities in the 1° simulations are compensated by an overestimated sill cross-section, whereas it is too small in 1/3°. As such, the 1/3° and 1° simulations show both large under- and overestimations of volume transport at several locations. No significant improvement in modeled overflows takes place when the grid spacing is decreased from 1° to 1/3°. An experiment conducted with hand-tuned topography shows improved volume transports near the regions of modification, but somewhat increased errors in other parts of the deep circulation, indicating the complex response of the system to perturbations in bathymetry. These results demonstrate the importance of an accurate representation of the domain geometry, in particular the channels of the complex Iceland–Scotland ridge system, in order to reproduce the pathways of the deep AMOC. [Copyright &y& Elsevier]

Abstract: Mixing of overflows released from polar and marginal seas is a key process shaping the structure of the meridional overturning circulation. Ocean general circulation models have difficulty in resolving the overflows, and therefore they must rely on parameterizations. In this study, the performance of a set of turbulence closures in reproducing mixing of an overflow is quantified. We simulate the Red Sea overflow by employing standard k–ε, k–ω and Mellor–Yamada schemes with various stability functions, as well as a modified k–ε model that relies on the prescription of the turbulent Prandtl number rather than on stability functions. The simpler KPP mixing scheme and experiments without turbulent fluxes serve as useful references. To our knowledge, this is the first time that the performance of two-equation turbulence models has been examined so closely using data from an overflow. It is found that without turbulence closures, the hydrodynamic model has difficulty in reproducing the correct three-dimensional pathway of the Red Sea overflow, consisting of a distinct bifurcation into two diverging channels. All turbulence models capture the vertical structure of this overflow consisting of an interfacial layer, characterized by the density gradient, and a well-mixed bottom layer. Mean eddy diffusivity values from most closures are comparable those from observations. But we find that KPP leads to eddy diffusivity values that are too small while those from Mellor–Yamada with Galperin [Galperin, B., Kantha, L.H., Hassid, S., Rosati, A., 1988. A quasi-equilibrium turbulent energy model for geophysical flows. J. Atmos. Sci. 45, 55–62] stability functions are too large. Such high diffusivities lead to excessive mixing in the bottom layer of the overflow, ultimately resulting in a salinity deficit of approximately 1psu in the product water mass. Salinity deviations between the models and observations are quantified using both data taken along the channels and two sections across the overflow. KPP and Mellor–Yamada with Galperin (1988) stability functions produce the largest deviations from the observations, while the modified k–ε exhibits the smallest deviations. The other four closures fall in between, showing results similar to one another. The performance of the Mellor–Yamada turbulence closure is improved considerably by using the stability functions by Kantha and Clayson [Kantha, L.H., Clayson, C.A., 1994. An improved mixed layer model for geophysical applications. J. Geophys. Res. 99 (December), 25235–25266], which allow for a stationary Richardson number of 0.21. In conclusion, we find that most turbulence closures lead to a satisfactory reproduction of the Red Sea overflow, within the temporal and spatial sampling uncertainties of the REDSOX data, provided that fairly high-resolution regional models are used. [Copyright &y& Elsevier]

The outflow of warm, salty, and dense water from the Red Sea into the western Gulf of Aden is numerically simulated using the Hybrid Coordinate Ocean Model (HYCOM). The pathways of the modeled overflow, temperature, salinity, velocity profiles from stations and across sections, and transport estimates are compared to those observed during the 2001 Red Sea Outflow Experiment. As in nature, the simulated outflow is funneled into two narrow channels along the seafloor. The results from the three-dimensional simulations show a favorable agreement with the observed temperature and salinity profiles along the channels. The volume transport of the modeled overflow increases with the increasing distance from the southern exit of the Bab el Mandeb Strait due to entrainment of ambient fluid, such that the modeled transport shows a reasonable agreement with that estimated from the observations. The initial propagation speed of the outflow is found to be smaller than the estimated interfacial wave speed. The slow propagation is shown to result from the roughness of the bottom topography characterized by a number of depressions that take time to be filled with outflow water. Sensitivities of the results to the horizontal grid spacing, different entrainment parameterizations, and forcing at the source location are investigated. Because of the narrow widths of the approximately 5 km of the outflow channels, a horizontal grid spacing of 1 km or less is required for model simulations to achieve a reasonable agreement with the observations. Comparison of two entrainment parameterizations, namely, TPX and K-profile parameterization (KPP), show that similar results are obtained at 1-km resolution. Overall, the simulation of the Red Sea outflow appears to be more strongly affected by the details of bottom topography and grid spacing needed to adequately resolve them than by parameterizations of diapycnal mixing. [ABSTRACT FROM AUTHOR]

Abstract: Mixing between overflows and ambient water masses is a critical problem of deep-water mass formation in the downwelling branch of the meridional overturning circulation of the ocean. Modeling approaches that have been tested so far rely either on algebraic parameterizations in hydrostatic ocean circulation models, or on large eddy simulations that resolve most of the mixing using nonhydrostatic models. In this study, we examine the performance of a set of turbulence closures, that have not been tested in comparison to observational data for overflows before. We employ the so-called very large eddy simulation (VLES) technique, which allows the use of models in nonhydrostatic models. This is done by applying a dynamic spatial filtering to the equations. To our knowledge, this is the first time that the VLES approach is adopted for an ocean modeling problem. The performance of and VLES models are evaluated by conducting numerical simulations of the Red Sea overflow and comparing them to observations from the Red Sea Outflow Experiment (REDSOX). The computations are constrained to one of the main channels transporting the overflow, which is narrow enough to permit the use of a two-dimensional (and nonhydrostatic) model. A large set of experiments are conducted using different closure models, Reynolds numbers and spatial resolutions. It is found that, when no turbulence closure is used, the basic structure of the overflow, consisting of a well-mixed bottom layer (BL) and entraining interfacial layer (IL), cannot be reproduced. The model leads to unrealistic thicknesses for both BL and IL, while VLES results in the most realistic reproduction of the REDSOX observations. [Copyright &y& Elsevier]

Abstract: Building on the work by Turner [Turner, J.S., 1986. The development of the entrainment assumption and its application to geophysical flows. J. Fluid Mech. 173, 431–471] and Hallberg [Hallberg, R., 2000. Time integration of diapycnal diffusion and Richardson number dependent mixing in isopycnal coordinate ocean models. Mon. Weather Rev. 128, 1402–1419], an algebraic parameterization of the entrainment process in gravity current has been derived for isopycnic coordinate ocean models. It casts the entrainment into layers as a function of the layer Richardson number (Ri) times the velocity difference across layers. In order to determine the function f(Ri), simulations of generic gravity currents over various bottom slope angle are conducted with the HYbrid Coordinate Ocean Model (HYCOM) and compared to similar experiments with the high-resolution, three-dimensional, nonhydrostatic model Nek5000, which serves as ground truth. A simple linear function, E =0.20(1− Ri/0.25), is found to reproduce quite well the entrainment, salt flux, Richardson number, velocity profile and plume propagation speed in Nek5000. The parameterization is then applied to a realistic-topography simulation of the Mediterranean outflow with HYCOM and shown to produce realistic equilibration depth and water mass properties of the outflow plume. [Copyright &y& Elsevier]

Given the motivation that overflow processes, which supply source waters for most of the deep and intermediate water masses in the ocean, pose significant numerical and dynamical challenges for ocean general circulation models, an intercomparison study is conducted between field data collected in the Red Sea overflow and a high-resolution, nonhydrostatic process model. The investigation is focused on the part of the outflow that flows along a long narrow channel, referred to as the “northern channel,” that naturally restricts motion in the lateral direction such that the use of a two-dimensional model provides a reasonable approximation to the dynamics. This channel carries about two-thirds of the total Red Sea overflow transport, after the overflow splits into two branches in the western Gulf of Aden. The evolution of the overflow in the numerical simulations can be characterized in two phases: the first phase is highly time dependent, during which the density front associated with the overflow propagates along the channel. The second phase corresponds to that of a statistically steady state. The primary accomplishment of this study is that the model adequately captures the general characteristics of the system: (i) the gradual thickening of the overflow with downstream distance, (ii) the advection of high salinity and temperature signals at the bottom along the channel with little dilution, and (iii) ambient water masses sandwiched between the overflow and surface mixed layer. To quantify mixing of the overflow with the ambient water masses, an entrainment parameter is determined from the transport increase along the slope and is expressed explicitly as a function of mean slope angle. Bulk Richardson numbers are estimated both from data and model and are related to the entrainment parameter. The range of entrainment parameter and its functional dependence on bulk Richardson number in this study are found to be in reasonable agreement with those reported from various laboratory experiments and that based on measurements of the Mediterranean overflow. The results reveal a complex dynamical interaction between shear-induced mixing and internal waves and illustrate the high computational and modeling requirements for numerical simulation of overflows to capture (at least in part) turbulent transports explicitly. [ABSTRACT FROM AUTHOR]

The Mediterranean Water leaves the western end of the Strait of Gibraltar as a bottom wedge of salty and warm waters flowing down the continental slope. The salinity of the onset Mediterranean Outflow Water (MOW) is so high that leads to water much denser (initially in excess of 1.5 kg m −3 ) than the overlying central waters. During much of its initial descent, the MOW retains large salinity anomalies – causing density anomalies that induce its gravity current character – and relatively high westward speeds – causing a substantial Coriolis force over long portions of its course. We use hydrographic data from six cruises (a total of 1176 stations) plus velocity data from two cruises, together with high-resolution bathymetric data, to track the preferential MOW pathways from the Strait of Gibraltar into the western Gulf of Cadiz and to examine the relation of these pathways to the bottom topography. A methodology for tributary systems in drainage basins, modified to account for the Coriolis force, emphasizes the good agreement between the observed trajectories and those expected from a topographically-constrained flow. Both contour avenues and cross-slope channels are important and have complementary roles steering the MOW along the upper and middle continental slope before discharging as a neutrally buoyant flow into the western Gulf of Cadiz. Our results show that the interaction between bottom flow and topography sets the path and final equilibrium depths of the modern MOW. Furthermore, they support the hypothesis that, as a result of the high erosive power of the bottom flow and changes in bottom-water speed, the MOW pathways and mixing rates have changed in the geological past. [ABSTRACT FROM AUTHOR]

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder of tooth development which is due to aberrant deposition or composition of enamel. Both syndromic and isolated forms exist; they may be inherited in an X-linked, autosomal recessive, or autosomal dominant manner. WDR72 is one of ten currently known genes for recessive isolated AI; nine WDR72 mutations affecting single nucleotides have been described to date. Based on whole exome sequencing in a large consanguineous AI pedigree, we obtained evidence for presence of a multi-exonic WDR72 deletion. A home-made multiplex ligation-dependent probe amplification assay was used to confirm the aberration, to narrow its extent, and to identify heterozygous carriers. Our study extends the mutational spectrum for WDR72 to include large deletions, and supports a relevance of the previously proposed loss-of-function mechanism. It also introduces an easy-to-use and highly sensitive tool for detecting WDR72 copy number alterations. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by heterozygotic inactivation of the NF1 tumor suppressor gene at 17q11.2. The associated phenotypes are highly variable, and modifying genes have been proposed to explain at least in part the intriguing expressivity. Given that haploinsufficiency of the NF1 gene product neurofibromin is responsible for some of the clinical manifestations, variations in expression of the wildtype NF1 allele might modify the phenotype. We therefore investigated epigenetic molecular modifications that could result in variable expression of the normal NF1 allele. To exclude confounding by DNA sequence variations, we analyzed monozygotic twin pairs with NF1 who presented with several discordant features. We fine-mapped the methylation pattern of a nearly 1 kb NF1 promoter region in lymphocytes of 8 twin pairs. All twin pairs showed significant intra-pair differences in methylation, especially of specific promoter subregions such as 5'UTR, exon 1 and intron 1 (+7 to +622), transcription factor binding sites and promoter elements like NF1HCS. Furthermore, we detected significant intra-pair differences in cytosine methylation for the region from -249 to -234 with regard to discordance for optic glioma with a higher grade of methylation in glioma cases. In conclusion, our findings of epigenetic differences of the NF1 promoter in leukocytes within mono zygotic twin pairs may serve as a proof of principle for other tissues. The results point towards a role of methylation patterns of the normal NF1 allele for expression differences and for modification of the NF1 phenotype. [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype–phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant cell lesion formation in patients with NS and CFCS rather than specific mutation effects.European Journal of Human Genetics (2009) 17, 420–425; doi:10.1038/ejhg.2008.188; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

Congenital central hypoventilation syndrome (CCHS), a rare disorder typically presenting in the newborn period, results in over 90% of cases from PHOX2B polyalanine repeat mutations. It is characterized by alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung’s disease and, later, tumors of neural crest origin. We describe a preterm infant with severe phenotype of CCHS and hyperinsulinism. A novel de novo heterozygote missence mutation (Gly68Cys) in the PHOX2B gene could be identified. Based on the observation of three patients presenting with the combination of congenital hyperinsulinism and CCHS, hyperinsulinism might represent an additional clinical feature of CCHS. [ABSTRACT FROM AUTHOR]

We report on a young female patient with the clinical features of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, OMIM 110100) and a balanced chromosome translocation 46, XX, t(2;3)(q33;q23)dn.BPES is a rare autosomal dominant congenital disorder characterized by the eponymous oculo-facial features that are, in female patients, associated either with (type 1 BPES) or without (type 2 BPES) premature ovarian failure. Both types of BPES are caused by heterozygous mutations in the FOXL2 gene, which is located in chromosome band 3q23. Chromosome aberrations such as balanced rearrangements have only rarely been observed in BPES patients but can provide valuable information about regulatory regions of FOXL2. The translocation in this patient broadens our knowledge of pathogenic mechanisms in BPES and highlights the importance of conventional cytogenetic investigations in patients with negative results of FOXL2 mutation screening as a prerequisite for optimal management and genetic counseling. [ABSTRACT FROM AUTHOR]

Hydrographic, direct velocity, and subsurface float observations from the 2001 Red Sea Outflow Experiment (REDSOX) are analyzed to investigate the gravitational and dynamical adjustment of the Red Sea Outflow Water (RSOW) where it is injected into the open ocean in the western Gulf of Aden. During the winter REDSOX cruise, when outflow transport was large, several intermediate-depth salinity maxima (product waters) were formed from various bathymetrically confined branches of the outflow plume, ranging in depth from 400 to 800 m and in potential density from 27.0 to 27.5 σθ, a result of different mixing intensity along each branch. The outflow product waters were not dense enough to sink to the seafloor during either the summer or winter REDSOX cruises, but analysis of previous hydrographic and mooring data and results from a one-dimensional plume model suggest that they may be so during wintertime surges of strong outflow currents, or about 20% of the time during winter. Once vertically equilibrated in the Gulf of Aden, the shallowest RSOW was strongly influenced by mesoscale eddies that swept it farther into the gulf. The deeper RSOW was initially more confined by the walls of the Tadjura Rift, but eventually it escaped from the rift and was advected mainly southward along the continental slope. There was no evidence of a continuous boundary undercurrent of RSOW similar to the Mediterranean Undercurrent in the Gulf of Cadiz. This is explained by considering 1) the variability in outflow transport and 2) several different criteria for separation of a jet at a sharp corner, which indicate that the outflow currents should separate from the boundary where they are injected into the gulf. [ABSTRACT FROM AUTHOR]

Abstract: In light of the pressing need for development and testing of reliable parameterizations of gravity current entrainment in ocean general circulation models, two existing entrainment parameterization schemes, K-profile parameterization (KPP) and one based on Turner’s work (TP), are compared using idealized experiments of dense water flow over a constant-slope wedge using the HYbrid Coordinate Ocean Model (HYCOM). It is found that the gravity current entrainment resulting from KPP and TP differ significantly from one another. Parameters of KPP and TP are then calibrated using results from the high-order nonhydrostatic spectral element model Nek5000. It is shown that a very good agreement can be reached between the HYCOM simulations with KPP and TP, even though these schemes are quite different from each other. [Copyright &y& Elsevier]

Purpose: Germline mutations in either BRCA1 or BRCA2 genes are responsible for the majority of hereditary breast and ovarian cancers. At present, over thousand distinct BRCA1 and BRCA2 mutations have been identified. Specific mutations are found to be common within particular populations, resulting from genetic founder effects. To investigate the contribution of germline mutations in these two genes to inherited breast cancer in Iran, we performed BRCA1/BRCA2 mutation analyses in ten Iranian high risk breast cancer families. This is the first study analysing the complete coding sequences of both genes that concerns the Iranian population. Methods: BRCA1/BRCA2 mutation detection included sequencing of the coding and the 3′ and 5′ untranslated regions. To detect large genomic rearrangements in the BRCA1 gene semi-quantitative multiplex PCR was performed. Results: Two pathogenic mutations in the BRCA2 gene were detected: a novel deletion c.4415_4418delAGAA and a previously described insertion c.6033_6034insGT. In addition, one intronic variation g.5075–53C>T and a deletion/insertion g.*381_389del9ins29 in the 3′ untranslated region of BRCA1 were found in two of the investigated families. Both sequence alterations were absent in an age matched Iranian control group. The BRCA2 homozygous variation p.N372H, previously associated with an increased risk for developing breast cancer, was not identified in this study. We did not detect large genomic rearrangements in BRCA1 in patients tested negatively for disease causing mutations in both genes by standard sequencing. Conclusions: At present, the BRCA2 mutations c.4415_4418delAGAA and c.6033_6034insGT have not been identified in any investigated population except the Iranian. Whether both mutations are specific for the Iranian population or a special subgroup remains to be investigated in larger studies. The absence of BRCA1 mutations in the analysed families may suggest that penetrance or prevalence of BRCA1 mutations may be lower in Iran. [ABSTRACT FROM AUTHOR]

Ectodermal dysplasias caused by mutations in the TP63 gene comprise a group of disorders characterized by a spectrum of ectodermal changes, orofacial clefting, and split hand or foot malformation. We report on a boy with a mutation located in the DNA-binding domain of the TP63 gene with atypical phenotype. These data provide additional evidence of the great variability seen in TP63-related disorders and further delineation of genotype-phenotype correlations. [ABSTRACT FROM AUTHOR]

Cherubism (MIM 118400) is an autosomal dominant inherited syndrome characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, which causes a characteristic facial swelling. Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism. [ABSTRACT FROM AUTHOR]

Examines the mutational spectrum of the entire neurofibromatosis type 1 gene. Aberrations in the coding sequence and splice sites; Distribution of whole gene from exon 1 to exon 47; Identification of clustered missense in two genetic regions.

Examines the gene mapping of cherubism to chromosome 4p16. Definition of cherubism in relation to development and eruption; Description of disorder; Use of genomewide search on genetic tracing and establishment of linkage to chromosome 4p16.