2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3

2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-Mb terminal microdeletion could be narrowed down to the same ∼ 200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37

Mutations in FKBP10 can cause a severe form of isolated Osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>FKBP10 </it>gene were first described in patients with Osteogenesis imperfecta type III. Two follow up reports found <it>FKBP10 </it>mutations to be associated with Bruck syndrome type 1, a rare disorder characterized by congenital contractures and bone fragility. This raised the question if the patients in the first report indeed had isolated Osteogenesis imperfecta or if Bruck syndrome would have been the better diagnosis.</p> <p>Methods</p> <p>The patients described here are affected by severe autosomal recessive Osteogenesis imperfecta without contractures.</p> <p>Results</p> <p>Homozygosity mapping identified <it>FKBP10 </it>as a candidate gene, and sequencing revealed a base pair exchange that causes a C-terminal premature stop codon in this gene.</p> <p>Conclusions</p> <p>Our study demonstrates that <it>FKBP10 </it>mutations not only cause Bruck syndrome or Osteogenesis imperfecta type III but can result in a severe type of isolated Osteogenesis imperfecta type IV with prenatal onset. Furthermore, it adds dentinogenesis imperfecta to the spectrum of clinical symptoms associated with <it>FKBP10 </it>mutations.</p

Risk estimation in families with Duchenne muscular dystrophy or Becker muscular dystrophy

Risikoberechnung in Familien mit Muskeldystrophie Duchenne oder Muskeldystrophie Becker. Unter Berücksichtigung eines Keimzellmosaiks, heterogener Neumutationsraten und der Möglichkeit homozygot betroffener Frauen.Risk estimation in families with Duchenne muscular dystrophy or Becker muscular dystrophy. Regarding germline mosaicism, specific mutation rates and homozygote affected women

Are scenarios of energy demand in the building stock in line with Paris targets?

COP21 led to an agreed target of keeping the increase in global average temperature well below 2 °C compared to pre-industrial levels. Due to its high potential for decarbonisation, the building stock will have to contribute a reduction of at least 85–95% in greenhouse gas (GHG) emissions until 2050. Policy-driven scenario analysis is, therefore, important for assisting policy makers who are called upon to develop a corresponding framework to achieve those targets. The research questions of this paper are (1) Do long-term scenarios (in particular those labelled as ambitious) of energy demand in buildings reflect the COP21 target? (2) If not: What are reasons for the gap in terms of scenario assumptions, in particular, regarding the policy framework in the corresponding scenarios? The method builds on following steps: (1) analysis of GHG-emission reduction in scenarios from the policy-driven, bottom-up model Invert/EE-Lab; (2) compare scenarios among each other and analyse if they are in line with Paris targets; (3) discuss possible explanations for any gaps and the implications on future modelling work and policy making. Results show that scenarios labelled as being “ambitious” for several EU MSs achieve GHG-emission reductions of 56–96% until 2050. However, just 27% of these ambitious scenarios achieve reductions above 85%. The reason is that policies for most of the modelled scenarios were developed together with policy makers and stakeholders, who—for different reasons—were not willing to go beyond a certain stringency in the modelled instruments. In particular, this was the case for regulatory instruments, which show to be essential for achieving ambitious climate targets

Nicotinic Acetylcholine Receptor Subunits α4 and α5 Associated with Smoking Behaviour and Lung Cancer Are Regulated by Upstream Open Reading Frames

<div><p>Nicotinic acetylcholine receptor subunits (nAChR) are associated with different aspects of smoking behaviour as well as with smoking related disorders. Several of these subunits have been found to be upregulated in smokers or differentially expressed in lung tumor cells. The mechanisms behind these observations are not known but assumed to be mainly post-transcriptional. Many post-transcriptional mechanisms are initiated by functionally relevant sequence motifs within untranslated gene regions, such as upstream open reading frames (uORFs). We performed a systematic search in all smoking-associated neuronal nAChR subunits and identified functionally relevant uORFs in <i>CHRNA4</i> and <i>CHRNA5</i>. Luciferase experiments showed that these uORFs are able to significantly decrease protein expression. Our quantitative real-time PCR (qPCR) results strongly suggest that the observed effects originate at the translation rather than at the transcription level. Interestingly, the <i>CHRNA4</i> uORF was only functionally relevant when expressed in the shorter isoform of this gene. Therefore, the data presented in this study strongly points towards an important role of uORFs within the 5′UTR of <i>CHRNA4</i>-isoform 1 and <i>CHRNA5</i> as regulators of protein translation. Moreover, the shared uORF of <i>CHRNA4</i>-isoform 1/isoform 2 represents the first example of a sequence context-dependent uORF.</p></div

Figure 1. 5

<p>′<b>UTRs of nicotine dependence-associated nAChR subunit genes with putative uORFs.</b> The bp position for each uORF (start/stop) is depicted starting from the main start codon in 5′- direction. <i>CHRNA4</i> isoform 1 and isoform 2 differ in their coding region, with a further downstream translation initiation for isoform 2, that elongates its 5′UTR. <i>CHRNA4</i> isoform 2 was not published until 2012 and has not been functionally analysed before. Squares, uORFs; arrows, SNPs</p

List of plasmid constructs for luciferase assay and qPCR.

1<p>coding sequence; ²guanine; ³adenine; +, present; −, non-functional</p

<b><i>CHRNA5</i></b><b> 5</b>

<p>′<b>UTR harbours a functional uORF; </b><b><i>CHRNB3</i></b><b> uORFs are not involved in translational control. </b><b>A:</b> Luciferase assay of <i>CHRNA5</i> 5′UTR resulted in significant increase in protein expression when switching off the uORF. Fold change of firefly activity normalized to pGl4.10 +TK, is illustrated for the five different constructs; 1, pGl4.10+TK; 2, <i>CHRNA5</i>-1; 3, <i>CHRNA5</i>-2; 4, <i>CHRNA5</i>-3; 5, <i>CHRNA5</i>-4. <b>B:</b> The uORF start codon of <i>CHRNA5</i> did not initiate translation as efficiently as the firefly start codon. Fold change of firefly activity normalized to pGl4.10 +TK, is illustrated for the five different constructs; 1, pGl4.10+TK; 2, pGL4.10; 3, <i>CHRNA5</i>-2; 4, <i>CHRNA5</i>-5; 5, <i>CHRNA5</i>-6. <b>C:</b> Relative qPCR for <i>CHRNA5</i> 5′UTR showed no significant differences of mRNA amount when comparing intact with deleted uORF. However, significant differences were assessed for the transcription of the two SNP allele variants. Fold change of firefly mRNA normalized to pGl4.10 +TK, is illustrated for the five different constructs; 1, pGl4.10+TK; 2, <i>CHRNA5</i>-1; 3, <i>CHRNA5</i>-2; 4, <i>CHRNA5</i>-3; 5, <i>CHRNA5</i>-4. <b>D:</b> Luciferase assay of <i>CHRNB3</i> 5′UTR showed no significant results. Fold change of firefly activity normalized to pGl4.10 +TK, is illustrated for the four different constructs; 1, pGl4.10+TK; 2, <i>CHRNB3</i>-1; 3, <i>CHRNB3</i>-2; 4, <i>CHRNB3</i>-3. Error bars represent ± SEM of 3 biological replicates. Asterisks indicate significant differences (<i>p</i><0.05).</p

<i>CHRNA4</i> isoform 1 contains a post-transcriptionally functional uORF, but not <i>CHRNA4</i> isoform 2.

<p><b>A:</b> Luciferase assay of <i>CHRNA4</i> isoform 1 5′UTR resulted in significant increase in protein expression when switching off the uORF. Fold change of firefly activity normalized to pGl4.10 +TK, is illustrated for the three different constructs; 1, pGl4.10+TK; 2, <i>CHRNA4</i>-iso1-1; 3, <i>CHRNA4</i>-iso1-2. <b>B:</b> The uORF ATG of <i>CHRNA4</i>-iso1 is able to initiate translation, resulting in an elongated firefly protein. Fold change of firefly activity normalized to pGl4.10 +TK, is illustrated for the five different constructs; 1, pGl4.10+TK; 2, pGl4.10; 3, <i>CHRNA4</i>-iso1-2; 4, <i>CHRNA4</i>-iso1-3; 5, <i>CHRNA4</i>-iso1-4. <b>C:</b> Relative qPCR for <i>CHRNA4-iso1</i> 5′UTR showed no significant differences of mRNA amount when comparing intact with deleted uORF. Fold change of firefly mRNA normalized to pGl4.10 +TK, is illustrated for the three different constructs; 1, pGl4.10+TK; 2, <i>CHRNA4</i>-iso1-1; 3, <i>CHRNA4</i>-iso1-2. <b>D:</b> None of the five uORFs of <i>CHRNA4</i>-iso2 5′UTR showed significant results. Fold change of firefly activity normalized to pGl4.10 +TK, is illustrated for the seven different constructs; 1, pGl4.10+TK; 2, <i>CHRNA4</i>-iso2-uORF1-5; 3, <i>CHRNA4</i>-iso2-uORF1; 4, <i>CHRNA4</i>-iso2-uORF2; 5, <i>CHRNA4</i>-iso2-uORF3; 6, <i>CHRNA4</i>-iso2-uORF4; 7, <i>CHRNA4</i>-iso2-uORF5. Error bars represent ± SEM of 3 biological replicates. Asterisks indicate significant differences (<i>p</i><0.05).</p

Organizer-Derived WOX5 Signal Maintains Root Columella Stem Cells through Chromatin-Mediated Repression of CDF4 Expression.

Stem cells in plants and animals are maintained pluripotent by signals from adjacent niche cells. In plants, WUSCHEL HOMEOBOX (WOX) transcription factors are central regulators of stem cell maintenance in different meristem types, yet their molecular mode of action has remained elusive. Here we show that in the Arabidopsis root meristem, the WOX5 protein moves from the root niche organizer, the quiescent center, into the columella stem cells, where it directly represses the transcription factor gene CDF4. This creates a gradient of CDF4 transcription, which promotes differentiation opposite to the WOX5 gradient, allowing stem cell daughter cells to exit the stem cell state. We further show that WOX5 represses CDF4 transcription by recruiting TPL/TPR co-repressors and the histone deacetylase HDA19, which consequently induces histone deacetylation at the CDF4 regulatory region. Our results show that chromatin-mediated repression of differentiation programs is a common strategy in plant and animal stem cell niches