305 research outputs found

    GTF2IRD1 regulates transcription by binding an evolutionarily conserved DNA motif ‘GUCE’

    Get PDF
    AbstractGTF2IRD1 is a member of a family of transcription factors whose defining characteristic is varying numbers of a helix–loop–helix like motif, the I-repeat. Here, we present functional analysis of human GTF2IRD1 in regulation of three genes (HOXC8, GOOSECOID and TROPONIN ISLOW). We define a regulatory motif (GUCE–GTF2IRD1 Upstream Control Element) common to all three genes. GUCE is bound in vitro by domain I-4 of GTF2IRD1 and mediates transcriptional regulation by GTF2IRD1 in vivo. Definition of this site will assist in identification of other downstream targets of GTF2IRD1 and elucidation of its role in the human developmental disorder Williams–Beuren syndrome

    Cellular and clinical impact of Haploinsufficiency for genes involved in ATR signaling

    Get PDF
    Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders--a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome--in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship

    Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients

    Get PDF
    Background Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed

    Exploring face perception in disorders of development: evidence from Williams syndrome and autism

    Get PDF
    Individuals with Williams syndrome (WS) and autism are characterized by different social phenotypes but have been said to show similar atypicalities of face-processing style. Although the structural encoding of faces may be similarly atypical in these two developmental disorders, there are clear differences in overall face skills. The inclusion of both populations in the same study can address how the profile of face skills varies across disorders. The current paper explored the processing of identity, eye-gaze, lip-reading, and expressions of emotion using the same participants across face domains. The tasks had previously been used to make claims of a modular structure to face perception in typical development. Participants with WS (N=15) and autism (N=20) could be dissociated from each other, and from individuals with general developmental delay, in the domains of eye-gaze and expression processing. Individuals with WS were stronger at these skills than individuals with autism. Even if the structural encoding of faces appears similarly atypical in these groups, the overall profile of face skills, as well as the underlying architecture of face perception, varies greatly. The research provides insights into typical and atypical models of face perception in WS and autism

    GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

    Get PDF
    COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.Peer reviewe

    Knowledge sharing for innovation performance improvement in micro/SMEs: an insight from the creative sector

    Get PDF
    As economies become more reliant on innovative, knowledge-intensive firms, understanding the interaction between knowledge and improving innovation performance is increasingly important. Although most UK businesses are micro, small or medium-sized enterprises (micro/SMEs), knowledge management research has tended to focus on large companies Knowledge sharing can be critical for innovation performance, especially for smaller players with limited resources. Our study presents an insight from micro/SMEs operating in the highly knowledge-intensive and innovative games/entertainment software development sector. Using a mixed method approach, we investigate knowledge sharing and its contribution to firm innovation performance improvements. Our findings suggest that micro/SMEs are at the forefront of the creative sector precisely because of their smaller size. Our study reveals evidence of knowledge donation but limited evidence of knowledge collection in the knowledge sharing process. We develop a model highlighting the importance of industry context, individual knowledge and organizational size in knowledge sharing for innovation performance

    A MITF Mutation Associated with a Dominant White Phenotype and Bilateral Deafness in German Fleckvieh Cattle

    Get PDF
    A dominantly inherited syndrome associated with hypopigmentation, heterochromia irides, colobomatous eyes and bilateral hearing loss has been ascertained in Fleckvieh cattle (German White Fleckvieh syndrome). This syndrome has been mapped to bovine chromosome (BTA) 22 using a genome-wide association study with the bovine high density single nucleotide polymorphism array. An R210I missense mutation has been identified within microphthalmia-associated transcription factor (MITF) as responsible for this syndrome. The mutation is located in the highly conserved basic region of the protein and causes a negative-dominant effect. SOX10 and PAX3 promoter binding site mutations in MITF could be ruled out as causative for the German White Fleckvieh syndrome. Molecular characterization of this newly detected bovine syndrome means a large animal model is now available for the Tietz syndrome in humans
    • …
    corecore