Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

BACKGROUND: PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. METHODS: Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. RESULTS: We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. CONCLUSION: Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype

Entrepreneurship and social capital: examining the association in deprived urban neighbourhoods

Spatial approaches to examining entrepreneurship have increasingly built on theories of social capital. However, the nature and extent of local social capital in less successful deprived communities remains under-researched and inadequately understood. The paper examines the association between social capital and entrepreneurship in a deprived urban neighbourhood in the city of Leeds, UK as a means of contributing to an improved theoretical understanding of how space moderates this association. It is found that social capital has a strong association with patterns of entrepreneurship in deprived urban neighbourhoods, with the potential impacts being both positive and negative. The forms of social capital are found to differ from that found in more affluent localities, with a prevalence of bonding social capital as the key facilitator of entrepreneurship, which may help in the early stages of venture development, but which over time may become a constraint. Also, a lack of the bridging social capital associated with entrepreneurial success is found within the locality. From a policy perspective, it is recommended that policy makers responsible for entrepreneurship in deprived urban neighbourhoods should seek to enhance initiatives for developing social capital which incorporate local businesses, residents and local government agencies

Mixed marriages and transnational families in the intercultural context : a case study of African-Spanish couples in Catalonia, Spain

Premi a l'excel·lència investigadora. Àmbit de les Ciències Socials. 2008One of the consequences of international migration and the permanent settlement of immigrants in southern EU countries is the growing number of inter-country marriages and the formation of transnational families. Using both quantitative and qualitative data, this article examines patterns of endogamy and exogamy (i.e. marriage within/outside a particular group or category) among African immigrants in Catalonia, focusing on bi-national Senegalese- and Gambian-Spanish couples. Socio-demographic profiles, transnationality, the dynamics of cultural change or retention, and the formation of transcultural identities are explored. The evidence presented suggests that social-class factors are more important than cultural origins in patterns of endogamy and exogamy, in the dynamics of living together and in the bringing-up of children of mixed unions. Such a conclusion negates culturalists' explanations of endogamy and exogamy while, at the same time, emphasising the role of social actors as active subjects in these processes. I further argue that mixed couples and their offspring deal-to a greater or lesser extent-with multiple localisations and cultural backgrounds (i.e. here and there), rather than experiencing a 'clash between two cultures'. Therefore, it would be a mistake to pretend that multicultural links do not exist and that they cannot be revitalised and functional. The paper starts and ends by addressing the complexities of processes of interculturalism, resisting an interpretation of hybridity and segregation as contradictory or exclusive realities

Molecular and electrophysiological characterization of anion transport in Arabidopsis thaliana pollen reveals regulatory roles for pH, Ca(2+) and GABA

We investigated the molecular basis and physiological implications of anion transport during pollen tube (PT) growth in Arabidopsis thaliana (Col-0). Patch-clamp whole-cell configuration analysis of pollen grain protoplasts revealed three subpopulations of anionic currents differentially regulated by cytoplasmic calcium ([Ca2+ ]cyt ). We investigated the pollen-expressed proteins AtSLAH3, AtALMT12, AtTMEM16 and AtCCC as the putative anion transporters responsible for these currents. AtCCC-GFP was observed at the shank and AtSLAH3-GFP at the tip and shank of the PT plasma membrane. Both are likely to carry the majority of anion current at negative potentials, as extracellular anionic fluxes measured at the tip of PTs with an anion vibrating probe were significantly lower in slah3-/- and ccc-/- mutants, but unaffected in almt12-/- and tmem16-/- . We further characterised the effect of pH and GABA by patch clamp. Strong regulation by extracellular pH was observed in the wild-type, but not in tmem16-/- . Our results are compatible with AtTMEM16 functioning as an anion/H+ cotransporter and therefore, as a putative pH sensor. GABA presence: (1) inhibited the overall currents, an effect that is abrogated in the almt12-/- and (2) reduced the current in AtALMT12 transfected COS-7 cells, strongly suggesting the direct interaction of GABA with AtALMT12. Our data show that AtSLAH3 and AtCCC activity is sufficient to explain the major component of extracellular anion fluxes, and unveils a possible regulatory system linking PT growth modulation by pH, GABA, and [Ca2+ ]cyt through anionic transporters.Patrícia Domingos, Pedro N. Dias, Bárbara Tavares, Maria Teresa Portes, Michael M. Wudick, Kai R. Konrad, Matthew Gilliham, Ana Bicho, and José A. Feij

Pollen Tube Growth Regulation by Free Anions Depends on the Interaction between the Anion Channel SLAH3 and Calcium-Dependent Protein Kinases CPK2 and CPK20.

Apical growth in pollen tubes (PTs) is associated with the presence of tip-focused ion gradients and fluxes, implying polar localization or regulation of the underlying transporters. The molecular identity and regulation of anion transporters in PTs is unknown. Here we report a negative gradient of cytosolic anion concentration focused on the tip, in negative correlation with the cytosolic Ca2+ concentration. We hypothesized that a possible link between these two ions is based on the presence of Ca2+-dependent protein kinases (CPKs). We characterized anion channels and CPK transcripts in PTs and analyzed their localization. Yellow fluorescent protein (YFP) tagging of a homolog of SLOW ANION CHANNEL-ASSOCIATED1 (SLAH3:YFP) was widespread along PTs, but, in accordance with the anion efflux, CPK2/CPK20/CPK17/CPK34:YFP fluorescence was strictly localized at the tip plasma membrane. Expression of SLAH3 with either CPK2 or CPK20 (but not CPK17/CPK34) in Xenopus laevis oocytes elicited S-type anion channel currents. Interaction of SLAH3 with CPK2/CPK20 (but not CPK17/CPK34) was confirmed by Förster-resonance energy transfer fluorescence lifetime microscopy in Arabidopsis thaliana mesophyll protoplasts and bimolecular fluorescence complementation in living PTs. Compared with wild-type PTs, slah3-1 and slah3-2 as well as cpk2-1 cpk20-2 PTs had reduced anion currents. Double mutant cpk2-1 cpk20-2 and slah3-1 PTs had reduced extracellular anion fluxes at the tip. Our studies provide evidence for a Ca2+-dependent CPK2/CPK20 regulation of the anion channel SLAH3 to regulate PT growth