Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε)

The 17p13.3 chromosome region is often deleted or duplicated in humans, resulting in severe neurodevelopmental disorders such as Miller–Dieker syndrome (MDS) and 17p13.3 duplication syndrome. Lissencephaly can also be caused by gene mutations or deletions of a small piece of the 17p13.3 region, including a single gene or a few genes. PAFAH1B1 gene, coding for LIS1 protein, is a responsible gene for lissencephaly and MDS and regulates neuronal migration by controlling microtubules (MTs) and cargo transport along MTs via dynein. CRK is a downstream regulator of the reelin signaling pathways and regulates neuronal migration. YWHAE, coding for 14-3-3ε, is also responsible for MDS and regulates neuronal migration by binding to LIS1-interacting protein, NDEL1. Although these three proteins are known to be responsible for neuronal migration defects in MDS, there are 23 other genes in the MDS critical region on chromosome 17p13.3, and little is known about their functions in neurodevelopment, especially in neuronal migration. This review will summarize the recent progress on the functions of LIS1, CRK, and 14-3-3ε and describe the recent findings of other molecules in the MDS critical regions in neuronal migration.

Identification of a Novel KRT9 Frameshift Mutation in a Chinese Pedigree with Epidermolytic Palmoplantar Keratoderma

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis caused by variants of keratin 9 (KRT9) or KRT1 gene. In this study causative gene mapping in a Chinese EPPK family was performed with Two-point linkage analysis and haplotyping. Positive linkage results were obtained on 17q (Zmax=2.06, θmax=0.0) at D17S799, which indicated KRT9 to be the most responsible gene for the family. Subsequently, direct sequencing identified a novel frameshift mutation caused by a 5bp deletion (∆GGAGG) in KRT9 in all affected individuals but not in the unaffected members or the 50 unrelated controls. The frameshift changed the encoding of the following nine amino acids and resulted in a readthrough translation in exon 7. The data revealed that the novel frameshift mutation in KRT9 was responsible for the Chinese EPPK pedigree. The researchers’ findings broaden the spectrum of KRT9 variants and provide further evidence for the highly genetic heterogeneity of EPPK.

Targeted CRISPR/Cas9-Based Knock-Out of the Rice Orthologs TILLER ANGLE CONTROL 1 (TAC1) in Poplar Induces Erect Leaf Habit and Shoot Growth

Pyramidal-, erect- or upright-growing plant forms are characterized by narrow branch angles of shoots and leaves. The putative advantage of upright-leaf and shoot habit could be a more efficient penetration of light into lower canopy layers. Pyramidal genotypes have already been reported for various tree genotypes including peach. The paralogous rice ortholog TILLER ANGLE CONTROL 1 (TAC1) has been proposed to be the responsible gene for upright growth. However, it has not really been demonstrated for any of the pyramidal tree genotypes that a knock-out mutation of the TAC1 gene is causing pyramidal plant growth. By in silico analyses, we have identified a putative rice TAC1 ortholog (Potri.014G102600, “TAC-14”) and its paralog (Potri.002G175300, “TAC-2”) in the genome of P. trichocarpa. Two putative PcTAC1 orthologs in the P. × canescens clone INRA 717-1B4 were successfully knocked-out by applying a transgenic CRISPR/Cas9-approach. The mutants were molecularly analyzed and phenotyped over a period of three years in a glasshouse. Our results indicate that the homozygous knock-out of “TAC-14” is sufficient to induce pyramidal plant growth in P. × canescens. If up to twice as many pyramidal individuals were planted on short rotation coppices (SRCs), this could lead to higher wood yield, without any breeding, simply by increasing the number of trees on a default field size.

Glypican-6 deficiency causes dose-dependent conotruncal congenital heart malformations through abnormal remodelling of the endocardial cushions

Tetralogy of Fallot (TOF) is considered to be the commonest type of cyanotic congenital heart disease (CHD). A previous GWAS showed significant association between TOF and single nucleotide polymorphisms in chromosome 13q31. Here through integration of population genomic and chromosomal interaction data we identify the heparan sulfate proteoglycan glypican-6 (GPC6) as the potentially responsible gene at the associated locus. We showed that GPC6 is expressed in the endocardial cushions at the appropriate time in development to contribute to TOF risk. We generated mice homozygous for a Gpc6 KO allele, which exhibit 100% neonatal lethality with severe cardiac malformations, namely TOF-type double outlet right ventricle (DORV) with rightward mal-positioned aorta and perimembranous ventricular septal defect (VSD), together with right ventricular (RV) hypertrophy and narrowing of the pulmonary artery. We established a dose-response relationship between Gpc6 expression and the anatomical severity of cardiac malformations. We showed the mouse knockout phenotype arises from abnormal morphology of the endocardial cushions, and tissue-specific knockout of Gpc6 in endothelial and neural crest cell lineages produces a phenotype featuring VSD and aortic malposition analogous to human TOF. This successful identification of a CHD gene from GWAS data suggests that larger GWA studies may find additional causative genes.

Genomic Markers for Essential Tremor

There are many reports suggesting an important role of genetic factors in the etiopathogenesis of essential tremor (ET), encouraging continuing the research for possible genetic markers. Linkage studies in families with ET have identified 4 genes/loci for familial ET, although the responsible gene(s) have not been identified. Genome-wide association studies (GWAS) described several variants in LINGO1, SLC1A2, STK32B, PPARGC1A, and CTNNA3, related with ET, but none of them have been confirmed in replication studies. In addition, the case-control association studies performed for candidate variants have not convincingly linked any gene with the risk for ET. Exome studies described the association of several genes with familial ET (FUS, HTRA2, TENM4, SORT1, SCN11A, NOTCH2NLC, NOS3, KCNS2, HAPLN4, USP46, CACNA1G, SLIT3, CCDC183, MMP10, and GPR151), but they were found only in singular families and, again, not found in other families or other populations, suggesting that some can be private polymorphisms. The search for responsible genes for ET is still ongoing.

A comprehensive interaction study provides a potential domain interaction network of human death domain superfamily proteins

Human death domain superfamily proteins (DDSPs) play important roles in many signaling pathways involved in cell death and inflammation. Disruption or constitutive activation of these DDSP interactions due to inherited gene mutations is closely related to immunodeficiency and/or autoinflammatory diseases; however, responsible gene mutations have not been found in phenotypical diagnosis of these diseases. In this study, we comprehensively investigated the interactions of death-fold domains to explore the signaling network mediated by human DDSPs. We obtained 116 domains of DDSPs and conducted a domain–domain interaction assay of 13,924 reactions in duplicate using amplified luminescent proximity homogeneous assay. The data were mostly consistent with previously reported interactions. We also found new possible interactions, including an interaction between the caspase recruitment domain (CARD) of CARD10 and the tandem CARD–CARD domain of NOD2, which was confirmed by reciprocal co-immunoprecipitation. This study enables prediction of the interaction network of human DDSPs, sheds light on pathogenic mechanisms, and will facilitate identification of drug targets for treatment of immunodeficiency and autoinflammatory diseases.

Genomic insight for Algicidal activity in Rhizobium sp. (AQ_MP)

Occurrence of Harmful Algal Blooms (HABs) creates a threat to aquatic ecosystem affecting the existing flora and fauna. Hence, the mitigation of HABs through an eco-friendly approach remains a challenge for environmentalists. The present study provides the genomic insights of Rhizobium sp. (AQ_MP), an environmental isolate that showed the capability of degrading Microcystis aeruginosa (Cyanobacteria) at laboratory scale. Genome sequence analysis of Rhizobium sp. (AQ_MP) was performed to determine the algal lysis properties and toxin degradative pathway. It is envisaged that Rhizobium sp. (AQ_MP) secreted CAZymes like Glycosyltransferases (GT), Glycoside Hydrolases (GH), polysaccharide lyases (PL), which allowed algal polysaccharide degradation (lysis) and enabled nutrient release for the subsequent growth of Rhizobium sp. (AQ_MP) Genome analysis also showed the presence of the glutathione metabolic pathway, which is the biological detoxification pathway responsible for microcystin degradation. The conserved region mlrC, a microcystin toxin degrading responsible gene, was also annotated in Rhizobium sp. (AQ_MP). This study confirmed that Rhizobium sp. (AQ_MP) harbours a wide range of crucial enzymes released for lysis of Microcystis aeruginosa (M. aeruginosa) cells and also for degradation of microcystin toxin. This study thus find promiscuity for scaling the lab based analysis to field level in future.

Goldberg-Shprintzen Syndrome Associated with a Novel Variant in the KIFBPGene

Goldberg-Shprintzen syndrome (GOSHS) is characterized by microcephaly, developmental delay, dysmorphic features, Hirschsprung disease (HSCR), and brain anomalies. The kinesin family binding protein (<i>KIFBP</i>; MIM 60937) gene has been identified as the responsible gene of the syndrome. To date, 16 different biallelic <i>KIFBP</i> mutations have been identified in 34 patients with GOSHS. Even though most of these mutations are nonsense and frameshift, 3 missense mutations have also been described. Here, we report an 18-month-old patient with microcephaly, developmental delay, dysmorphic features and HSCR. Exome analysis was performed to clarify the etiology of the clinical features. A previously unreported homozygous c.1723delC (p.H575Ifs*19) variant was detected in the last exon 7 of <i>KIFBP</i> which led to GOSHS. According to our findings, we suggest that this mutation expands mutational databases and contributes to the understanding of the phenotypic features of the syndrome.

Sindrome de allgrove en niños. Reporte de 11 casos

Background. Allgrove Syndrome is a very rare genetic disease, which is inherited in an autosomal recessive way. The responsible gene is the AAAS, that encodes the protein ALADIN. It occurs most often in children of consanguineous parents. It is characterized by the classic triad of achalasia, alacrima, and adrenal insufficiency due to resistance to ACTH; the presence of two of the three previous manifestation events are required to establish the diagnosis. There is also a high frequency of the neurologic symptoms. Objective. Describe the clinical characteristics, age of presentation and evolution in 11 patients with Allgrove Syndrome. Methods. 11 clinical cases compatible with Allgrove Syndrome of presentation in childhood are retrospectively reviewed. Results. The average age at diagnosis was 5.9 years (range 1-16 years old). There was a predominance of the female sex (n = 7). The most common symptoms were postprandial vomiting and alacrima, present in 100% of the cases at the time of diagnosis. Adrenal insufficiency was not common; it was only documented in one patient. There was consanguinity between parents in 62.5% of the cases. Conclusions. Allgrove Syndrome is an uncommon cause of dysphagia, chronic vomiting and failure to grow in children. In case of any documented case of achalasia it is suggested to question in a directed way the presence of alacrima and adrenal insufficiency data such as seizures, hyperpigmentation of the skin and neurological alterations.