Identification of 31 genomic loci for autosomal recessive mental retardation and molecular genetic characterization of novel causative mutations in four genes.

Severe mental and behavioral disorders are common, affecting 1-3% of the world populace. They thus constitute a major burden not only for the affected families but also for society. There is reason to believe that autosomal recessive mental retardation (ARMR) is more common than X-linked MR, but it has so far received considerably less attention. This is partly due to small family sizes and low consanguinity rates in industrialized societies, both of which have hampered gene mapping and identification, which is illustrated by the fact that until 2003, when this study was started, no more than one gene was shown to be implicated in non-syndromic ARMR (NS-ARMR). The work presented here is part of a larger project to shed more light on the molecular causes of ARMR as a prerequisite for diagnosis, counselling and therapy, focusing on large consanguineous Iranian families with several mentally retarded children. It combines clinical and molecular approaches such as patient recruitment, clinical characterization, sample collection, SNP array genotyping, whole genome linkage analysis, homozygosity mapping and finally mutation screening in a systematic fashion. Successful mutation detection is followed by functional analyses of the affected genes. In the study presented here, the investigation of 135 families led to the identification of 31 novel genomic loci for ARMR. Contrary to previous observations, which prima facie argued against the existence of frequently mutated genes, overlapping autozygosity regions from several families could now be observed on chromosomes 1, 5 and 19. At each of these loci a minimum of two overlapping linkage intervals were solitary in the respective families and showed a LOD score of, or above, three. Mutation screening in one of these families with NS-ARMR has led to the discovery of a new gene for NS-ARMR, TUSC3, where a mutation was found that leads to the loss of TUSC3 transcript in patient cells. Additional investigations in families with syndromic forms of ARMR revealed a new gene for ataxia and mild mental retardation. This gene, CA8, was found to carry a R237Q mutation, with a putatively deleterious effect on functional properties of the gene product in the affected patients. Furthermore one novel mutation in ALDH3A2 in patients with Sjögren-Larsson syndrome and two in the MCPH1 gene in patients with primary microcephaly were found. Gene expression profiling, knockdown experiments and irradiation studies added more evidence on the involvement of MCPH1 in cell cycle control, DNA damage response and transcriptional regulation. In summary, the identification of a novel gene for NS-ARMR and many new genomic intervals with a high probability for containing different genes with disease causing mutations is in keeping with previous results that indicated a high degree of genetic heterogeneity for this disorder. Still, the several overlapping loci found in this study now also indicate the presence of genes with an increased frequency of mutations in ARMR patients. Further studies are necessary to identify the disease causing mutations in these newly identified linkage intervals and to determine the contribution of the affected genes to the complex processes of human cognition. These studies will be greatly facilitated by the novel high throughput sequencing technologies, which are now available and that will allow a much increased pace for the detection of disease causing mutations

A method for solving an inverse biharmonic problem

AbstractThis paper deals with the problem of determining of an unknown coefficient in an inverse boundary value problem. Using a nonconstant overspecified data, it has been shown that the solution to this inverse problem exists and is unique

Evaluating knowledge, attitude and practice of Health-Care Workers regarding patient education in Iran

The objective of the study was to evaluate the position of patient education measuring knowledge, attitude, and practice (KAP) among health care workers (HCWs). It is also aimed to emphasize the need for a real position for patient education. This survey was performed among a group of HCWs in Iran. The scores had an acceptable level. However, nurses, females and younger people received higher scores. The staff was already aware of patient education necessity and considered it as the duty of all medical team. Often HCWs cannot include patient education in their routine due to time shortage, lack of staff�s financial motivation, fatigue, and loads of work, etc. There is still need for a real training in the educational curriculum. Additionally, the various HCWs�related obstacles should be taken into account. © 2015 Tehran University of Medical Sciences. All rights reserved

New kid on the ID block: Neural functions of the Nab2/ZC3H14 class of Cys3His tandem zinc-finger polyadenosine RNA binding proteins

Polyadenosine RNA binding proteins (Pabs) play critical roles in regulating the polyadenylation, nuclear export, stability, and translation of cellular RNAs. Although most Pabs are ubiquitously expressed and are thought to play general roles in post-transcriptional regulation, mutations in genes encoding these factors have been linked to tissue-specific diseases including muscular dystrophy and now intellectual disability (ID). Our recent work defined this connection to ID, as we showed that mutations in the gene encoding the ubiquitously expressed Cys3His tandem zinc-finger (ZnF) Pab, ZC3H14 (Zinc finger protein, CCCH-type, number 14) are associated with non-syndromic autosomal recessive intellectual disability (NS-ARID). This study provided a first link between defects in Pab function and a brain disorder, suggesting that ZC3H14 plays a required role in regulating RNAs in nervous system cells. Here we highlight key questions raised by our study of ZC3H14 and its ortholog in the fruit fly Drosophila melanogaster, dNab2, and comment on future approaches that could provide insights into the cellular and molecular roles of this class of zinc finger-containing Pabs. We propose a summary model depicting how ZC3H14-type Pabs might play particularly important roles in neuronal RNA metabolism

COMPETITION AMONG HOSPITALS AND ITS MEASUREMENT: THEORY AND A CASE STUDY

Our paper provides several insights on the characteristics of the concept of “Poles d’Excellence Rurale” (PER) through bilateral comparisons with that of Competitive Pole (CP) and cluster. The concept of PER is a French government’ initiative designed for the development of rural areas similar to that of the Competitive Pole. We emphasize important particularities of these concepts by analyzing some of their similarities and major differences.Pole d’Excellence Rurale, Competitive Pole, cluster, rural development

Strategies to Manage the Impacts of the COVID-19 Pandemic in the Supply Chain: Implications for Improving Economic and Social Sustainability

This paper aims to identify the negative impacts of the COVID-19 outbreak on supply chains and propose strategies to deal with the impacts in the context of the readymade garment (RMG) industry supply chain of an emerging economy: Bangladesh. To achieve the aims, a methodological framework is proposed through a literature review, expert inputs, and a decision-aid tool, namely the grey-based digraph-matrix method. A total of 10 types of negative impacts and 22 strategic measures to tackle the impacts were identified based on the literature review and expert inputs. Then, the grey-based digraph-matrix was applied for modeling the strategic measures based on their influence to deal with the impacts. Findings reveal that the strategies “manufacturing flexibility”, “diversify the source of supply”, and “develop backup suppliers” have significant positive consequences for managing the impacts of the COVID-19 pandemic in the RMG supply chain. The findings help industrial managers recover from supply chain disruptions by identifying and classifying the impacts and strategies required to manage the major supply chain disturbances caused by the COVID-19 pandemic. As a theoretical contribution, this study is one of few initial attempts to evaluate the impacts of the COVID-19 outbreak and the strategies to deal with the impacts in the supply chain context

Analyzing the Impact of Urban Planning and Building Typologies in Urban Heat Island Mitigation

Urban and building typologies have a serious impact on the urban climate and determine at large the magnitude of the urban overheating and urban heat island intensity. The present study aims to analyze the impact of various city typologies and urban planning characteristics on the mitigation of the urban heat island. The effect of the building height, street width, aspect ratio, built area ratio, orientation, and dimensions of open spaces on the distribution of the ambient and surface temperature in open spaces is analyzed using the Sydney Metropolitan Area as a case study for both unmitigated and mitigated scenarios. Fourteen precincts are developed and simulated using ENVI-met the simulation tool. The ambient temperature, surface temperature, and wind speed are extracted. The parameter ‘Gradient of the Temperature Decrease along the Precinct Axis’ (GTD) is introduced to study the cooling potential of the various precincts. In the mitigated precincts, the GTD ranges between 0.01 K/m to 0.004 K/m. In the non-mitigated precincts, the GTD ranges between 0.0093 K/m to 0.0024 K/m. A strong correlation is observed between the GTD of all the precincts, with and without mitigation, and their corresponding average aspect ratio, (Height of buildings to Width of streets). The higher the aspect ratio of the precinct, the lower the cooling potential. It is also observed that the higher the Built Area Ratio of the precincts, the lower the cooling contribution of the mitigation measures

Mutations in NSUN2 cause autosomal-recessive intellectual disability

With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227( *)] and c.1114C>T [p.Gln372( *)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs( *)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development

A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q

Objective: Developmental dyslexia is a highly heritable specific reading and writing disability. To identify a possible new locus and candidate gene for this disability, we investigated a four-generation pedigree where transmission of dyslexia is consistent with an autosomal dominant inheritance pattern. Methods: We performed genome wide array-based SNP genotyping and parametric linkage analysis and sequencing analysis of protein-coding exons, exon-intron boundaries and conserved extragenic regions within the haplotype cosegregating with dyslexia in DNA from one affected and one unaffected family member. Cosegregation was confirmed by sequencing all available family members. Additionally, we analyzed 96 dyslexic individuals who had previously shown positive LOD scores on chromosome 4q28 as well as an even larger sample (n = 2591). Results: We found a single prominent linkage interval on chromosome 4q, where sequence analysis revealed a nucleotide variant in the 3' UTR of brain expressed SPRY1 in the dyslexic family member that cosegregated with dyslexia. This sequence alteration might affect the binding efficiency of the IGF2BP1 RNA-binding protein and thus influence the expression level of the SPRY1 gene product. An analysis of 96 individuals from a cohort of dyslexic individuals revealed a second heterozygous variant in this gene, which was absent in the unaffected sister of the proband. An investigation of the region in a much larger sample further found a nominal p-value of 0.0016 for verbal short-term memory (digit span) in 2,591 individuals for a neighboring SNV. After correcting for the local number of analyzed SNVs, and after taking into account linkage disequilibrium, we found this corresponds to a p-value of 0.0678 for this phenotype. Conclusions: We describe a new locus for familial dyslexia and discuss the possibility that SPRY1 might play a role in the etiology of a monogenic form of dyslexia