ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response.

Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10-9). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations

ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

Abstract: Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10−9). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations

BBS4 is necessary for ciliary localization of TrkB receptor and activation by BDNF.

Primary cilia regulate an expanding list of signaling pathways in many different cell types. It is likely that identification of the full catalog of pathways associated with cilia will be necessary to fully understand their role in regulation of signaling and the implications for diseases associated with their dysfunction, ciliopathies. Bardet-Biedl Syndrome (BBS) is one such ciliopathy which is characterized by a spectrum of phenotypes. These include neural defects such as impaired cognitive development, centrally mediated hyperphagia and peripheral sensory defects. Here we investigate potential defects in a signaling pathway associated with neuronal function, brain derived neurotrophic factor (BDNF) signaling. Upon loss of BBS4 expression in cultured cells, we observed decreased phosphorylation and activation by BDNF of its target receptor, TrkB. Assessment of ciliary localization revealed that, TrkB localized to the axonemes or basal bodies of cilia only in the presence of BDNF. Axonemal localization, specifically, was abrogated with loss of BBS4. Finally, we present evidence that loss of the ciliary axoneme through depletion of KIF3A impedes activation of TrkB. Taken together, these data suggest the possibility of a previously uninvestigated pathway associated with perturbation of ciliary proteins

Altered Pax6 levels/activity differentially affect amacrine cell subtypes

gain-of-function (dark yellow bars) and loss-of-function (, light yellow bars) were induced at early (St. 12) and late (St. 16) eye field stages, and analyzed as in . gain-of-function at either eye field stage significantly reduced the D1.1.1 contribution to DA amacrine cells, whereas it only affected NPY cells at stage 12. loss-of-function at both stages significantly increased GABA cells and significantly decreased DA cells. NPY amacrine cells were not significantly affected by loss-of-function at either stage.<p><b>Copyright information:</b></p><p>Taken from "Changes in Rx1 and Pax6 activity at eye field stages differentially alter the production of amacrine neurotransmitter subtypes in "</p><p></p><p>Molecular Vision 2007;13():86-95.</p><p>Published online 26 Jan 2007</p><p>PMCID:PMC2503186.</p><p></p

The developmental programs that produce amacrine cell subtypes are differentially affected by Rx1 and Pax6 in a time-dependent manner

The effects on the number of amacrine cells produced after induction of the different Rx1 and Pax6 constructs at the two eye field stages are summarized. Retinal stem cells (RSC) in the stage 12 eye field are repressed by Rx1 from producing GABA and DA amacrine cells, but Rx1 is required for NPY amacrine cells. In contrast, Pax6 represses the production of DA and NPY amacrine cells. Loss-of-function of either Rx1 (by Rx1EnR) or Pax6 (by dnPax6) is required for GABA amacrine cell production. In the stage 16 eye field, which is likely comprised of both RSC and retinal progenitor cells (RPC) [], Rx1 continues to repress DA amacrine cells, but the effect on GABA amacrine cells is much reduced. In addition, Rx1 now represses NPY amacrine cells. Pax6 continues to repress DA cells, but the effect on NPY cells is no longer detectable. As at stage 12, loss-of-function of either Rx1 (by Rx1EnR) or Pax6 (by dnPax6) is required for GABA amacrine cell production. These data indicate that Rx1 and Pax6 differentially affect the production of the different amacrine subtypes over time. Because both genes are considered to be transcriptional activators [,], their inhibitory effects on amacrine subtypes are likely to be transcriptionally indirect.<p><b>Copyright information:</b></p><p>Taken from "Changes in Rx1 and Pax6 activity at eye field stages differentially alter the production of amacrine neurotransmitter subtypes in "</p><p></p><p>Molecular Vision 2007;13():86-95.</p><p>Published online 26 Jan 2007</p><p>PMCID:PMC2503186.</p><p></p

pTRKB in the ciliary axoneme is lost with depletion of <i>BBS4</i> expression.

<p>(A–G) Immunofluorescent staining of hTERT-RPE1 cells transfected with empty vector (EV), sh<i>BBS4</i> or both 3′UTR sh<i>BBS4</i> and <i>BBS4</i> expression construct. Cells were cultured in BDNF-supplemented media and stained using antibody against pTRKB (red) or ciliary markers labeling axoneme (ARL13B, green) or basal body (γ-tubulin, green). Region around cilia denoted by dashed box and magnified inset. Basal bodies highlighted by arrows and axoneme in (A,D) highlighted by arrowheads. Scale bar  = 10 µm. Imaged at 100× magnification. (H) Quantification of ciliary localization of pTRKB in transfected cells calculated as the proportion of either basal bodies or axonemes that co-localize with pTRKB. Error bars represent standard deviation. *significant difference (p<0.01, chi-square test).</p