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Sequencing of two mitochondrial genomes of endangered form of the Sevan trout Salmo ischchan aestivalis
3 July, 2018
The two complete mitochondrial genomes of endangered form of the Sevan trout Salmo ischchan aestivalis are published in this paper. The mitochondrial DNA (mtDNA) is 16,677 base pairs (bp) in length and contained 13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes. The overall base composition of the genome in descending order was 29.4% – C, 27.9% – A, 26.0% – T, 16.7% – G, without a significant AT bias of 53.9%.
Pages: 469-471 doi: 10.1080/23802359.2018.1462120
De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene
1 July, 2018
Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.
Pages: 1998-2013 doi: 10.1093/brain/awy145
Transcriptional networks of progressive diabetic peripheral neuropathy in the db/db mouse model of type 2 diabetes: An inflammatory story
1 July, 2018
Diabetic peripheral neuropathy is the most common complication of diabetes and a source of considerable morbidity. Numerous molecular pathways are linked to neuropathic progression, but it is unclear whether these pathways are altered throughout the course of disease. Moreover, the methods by which these molecular pathways are analyzed can produce significantly different results; as such it is often unclear whether previously published pathways are viable targets for novel therapeutic approaches. In the current study we examine changes in gene expression patterns in the sciatic nerve (SCN) and dorsal root ganglia (DRG) of db/db diabetic mice at 8, 16, and 24 weeks of age using microarray analysis. Following the collection and verification of gene expression data, we utilized both self-organizing map (SOM) analysis and differentially expressed gene (DEG) analysis to detect pathways that were altered at all time points. Though there was some variability between SOM and DEG analyses, we consistently detected altered immune pathways in both the SCN and DRG over the course of disease. To support these results, we further used multiplex analysis to assess protein changes in the SCN of diabetic mice; we found that multiple immune molecules were upregulated at both early and later stages of disease. In particular, we found that matrix metalloproteinase-12 was highly upregulated in microarray and multiplex data sets suggesting it may play a role in disease progression.
Pages: 33-43 doi: 10.1016/j.expneurol.2018.03.011
Reproductive, Physiological, and Molecular Outcomes in Female Mice Deficient in Dhh and Ihh
1 July, 2018
Ovarian development requires coordinate communications among oocytes, granulosa cells, and theca cells. Two Hedgehog (Hh) pathway ligands, Desert hedgehog (Dhh) and Indian hedgehog (Ihh), are produced by the granulosa cells and work together to regulate theca cell specification and development. Mice lacking both Dhh and Ihh had loss of normal ovarian function, which raised the question of which biological actions are specifically controlled by each ligand during folliculogenesis. By comparing the reproductive fitness, hormonal profiles, and ovarian transcriptomes among control, Dhh single-knockout (KO), Ihh KO, and Dhh/Ihh double-knockout (DKO) mice, we examined the specific roles of Dhh and Ihh in these processes. Dhh/Ihh DKO female mice were infertile because of a lack of theca cells and their steroid product androgen. Although Dhh and Ihh KO mice were fertile with normal folliculogenesis, they had decreased androgen production and alterations in their ovarian transcriptomes. Absence of Ihh led to aberrant steroidogenesis and elevated inflammation responses, which were not found in Dhh KO mouse ovaries, implicating that IHH has a greater impact than DHH on the activation of the Hh signaling pathway in the ovary. Our findings provide insight into not only how the Hh pathway influences folliculogenesis but also the distinct and overlapping roles of Dhh and Ihh in supporting ovarian development.
Pages: 2563-2575 doi: 10.1210/en.2018-00095
Transcriptomic Profiling of Obesity-Related Nonalcoholic Steatohepatitis Reveals a Core Set of Fibrosis-Specific Genes
1 July, 2018
Nonalcoholic steatohepatitis (NASH) is strongly associated with obesity and type 2 diabetes. The molecular factors underlying the development of inflammation and severe fibrosis in NASH remain largely unknown. The purpose of this study was to identify gene expression patterns related to obesity-related NASH inflammation and fibrosis. We performed sequencing-based mRNA profiling analysis of liver samples from individuals with normal histology (n = 24), lobular inflammation (n = 53), or bridging fibrosis, incomplete cirrhosis, or cirrhosis (n = 65). Hepatic expression of a subset of mRNAs was validated using an orthogonal method, analyzed in a hepatic stellate cell line, and used to identify transcriptional patterns shared by other forms of cirrhosis. We observed evidence for differential levels of 3820 and 2980 transcripts in lobular inflammation and advanced fibrosis, respectively, compared with normal histology (false discovery rate ≤0.05), including 176 genes specific to fibrosis. Functional enrichment analysis of these genes revealed participation in pathways involving cytokine-cytokine receptor interaction, PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix-receptor interaction. We identified 34 differentially expressed transcripts in comparisons of lobular inflammation and fibrosis, a proportion of which were also upregulated during activation of hepatic stellate cells. A set of 16 genes from a previous independent study of NASH bridging fibrosis/cirrhosis were replicated, several of which have also been associated with advanced fibrosis/cirrhosis due to hepatitis viruses or alcohol in human patients. Dysregulated mRNA expression is associated with inflammation and fibrosis in NASH. Advanced NASH fibrosis is characterized by distinct set of molecular changes that are shared with other causes of cirrhosis.
Pages: 710-726 doi: 10.1210/js.2018-00122