Genetics of intellectual disability in consanguineous families

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence

Quantification of thermal ring flexibilities of aromatic and heteroaromatic compounds

The consequences of thermal fluctuations occurring at room temperatures on the aromatic character of a broad group of compounds were analyzed in three distinct ways. First of all, the ring deformations were modeled along normal coordinates coming from quantum thermo-chemistry computations. The amplitudes of vibrations were estimated according to absorbed energies at room temperature. Alternatively, in-plane and out-of-plane ring deformations were modeled via scanning procedure with partial relaxation of the molecular geometry. The influence of ring deformations on π–electron delocalization was expressed in terms of HOMA values. Besides, the ring deformability was defined as the averaged change of bond angles or dihedral angles constituting the ring that was associated with 1.5 kcal mol-1 increase of the system energy. The molecules structures adopted during vibrations at room temperature can lead to significant heterogeneity of structural index of aromaticity. The broad span of HOMA values was obtained for analyzed five- or six-membered aromatic and heteroaromatic rings. However, the averaged values obtained for such fluctuations almost perfectly match HOMA values of molecule in the ground state. It has been demonstrated that the ring deformability imposed by bond angle changes is much smaller than for dihedral angles with the same rise of system energy. Interestingly in the case of out-of-plane vibrations modeled by scanning procedure there is observed linear correlation between ring deformability and HOMA values. Proposed method for inclusion of thermal vibrations in the framework of π–electron delocalization provides natural shift of the way of thinking about aromaticity from a static quantity to a dynamic and heterogeneous one due to inclusion of a more realistic object of analysis – thermally deformed structures. From this perspective the thermal fluctuations are supposed to be non-negligible contributions to aromaticity phenomenon

Biological influence of Hakai in cancer: a 10-year review

In order to metastasize, cancer cells must first detach from the primary tumor, migrate, invade through tissues, and attach to a second site. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells that is characterized as a potent tumor suppressor and is modulated during various processes including epithelial–mesenchymal transition. Recent data have provided evidences for novel biological functional role of Hakai during tumor progression and other diseases. Here, we will review the knowledge that has been accumulated since Hakai discovery 10 years ago and its implication in human cancer disease. We will highlight the different signaling pathways leading to the influence on Hakai and suggest its potential usefulness as therapeutic target for cancer

Apolipoprotein L1, income and early kidney damage

BACKGROUND: The degree to which genetic or environmental factors are associated with early kidney damage among African Americans (AAs) is unknown. METHODS: Among 462 AAs in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, we examined the cross-sectional association between apolipoprotein L1 (APOL1) risk variants and income with: 1) mildly reduced eGFR (<75 mL/min/1.73 m(2), creatinine-cystatin C equation) and 2) elevated urine albumin-to-creatinine ratio (ACR) (≥17 in men and ≥25 mg/g in women). High risk APOL1 status was defined by 2 copies of high-risk variants; low risk if 0 or 1 copy. Income groups were dichotomized as < $14,000/year (lowest income group) or ≥$14,000/year. Logistic regression models were adjusted for age, sex, and % European ancestry. RESULTS: Overall, participants’ mean age was 47 years and 16% (n = 73) had high risk APOL1 status. Mean eGFR was 99 mL/min/1.73 m(2). Mildly reduced eGFR was prevalent among 11% (n = 51). The lowest income group had higher adjusted odds (aOR) of mildly reduced eGFR than the higher income group (aOR 1.8, 95% CI 1.2-2.7). High-risk APOL1 was not significantly associated with reduced eGFR (aOR 1.5, 95% CI 0.9-2.5). Among 301 participants with ACR data, 7% (n = 21) had elevated ACR. Compared to low-risk, persons with high-risk APOL1 had higher odds of elevated ACR (aOR 3.8, 95% CI 2.0-7.3). Income was not significantly associated with elevated ACR (aOR 1.8, 95% CI 0.7-4.5). There were no significant interactions between APOL1 and income. CONCLUSIONS: Both genetic and socioeconomic factors may be important determinants of early kidney damage among AAs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12882-015-0008-6) contains supplementary material, which is available to authorized users

Molecular dynamics simulations combined with large angle X -ray scattering technique for the determination of structure, conformation and conformational dynamics of polyphosphazenzs in amorphous phase: study of poly(di-(4-methylphenoxy)phosphazene)

Suitable parameter sets for the CHARMm force field were derived using the Dinur-Hagler energy second-derivative procedure, on the basis of SCF calculations at the 6-31G* level, for the uncommon structural units in poly(phenoxyphosphazenes) [P=N, P-N, P-X (X=aryloxy)]. It is shown that application of molecular dynamics (MD) simulations, in combination with experimental energy dispersive X-ray diffraction (EDXD) measurements, provide unambiguous structural and conformational information on amorphous polymers. The procedure for the analysis of the EDXD data involves comparison of computed atom-atom radial distribution function (RDF) curve from MD simulations for the various polymer backbone conformations, with the RDF obtained from experimental X-ray scattering data. The applicability of this combined experimental/computational methodology is illustrated on the amorphous poly[di(4-methylphenoxy)phosphazene] (PMPP). The results showed that (i) the backbone conformation is safely [TC](n) rather than [T3C](n) and (ii) the computed RDFs are best assessed by using a MD simulation technique that avoids assumption of static chain conformation and the needed best fit of the distance dependent parameters s(jk). In this method of analysis, the RDF that to be compared with the experimental one is directly calculated from all microstates collected during the entire simulation period. Validation of the polymer model provides a complete picture, otherwise experimentally inaccessible, of the internal fluctuations of the polymeric hains. The computational protocol delineated for analysis of EDXD data is general and its application specifically necessary when highly flexible amorphous polymers are involved

Molecular Modelling and Large Angle X-ray Scattering (EDXD) Studies of the Structure of Semicrystalline Poly[bis(phenoxy)phosphazene]

The structure and conformation of semicrystalline poly[bis(phenoxy)phosphazene] (PBPP) was studied using molecular mechanics including ad hoc quantum mechanically derived force field (FF) parameters, in combination with the energy-dispersive X-ray diffraction (EDXD) technique. The atom-atom radial distribution function (RDF) curves were calculated for the various models of backbone conformations and for the structure in the crystalline a-form of PBPP. On the basis of comparison between theoretically calculated RDFs with the RDF obtained from the EDXD experiment, a model was proposed. The structural features of this model are (i) the polymer backbone adopts a low-energy, planar, trans-cis [TC], conformation, (ii) each chain is, on average, comprised of 16 monomeric units, and (iii) the unit cell may be restricted to contain two such chains running antiparallel to each other and with their backbones aligned parallel to the (1, 1, 0) Miller plane. The results demonstrate the capability of the combined use of computational chemistry (molecular modeling) and X-ray diffraction techniques such as EDXD to provide insights, otherwise experimentally inaccessible, into the conformational and structural features of semicrystalline polyphosphazenic materials