Biology subjects

Dean, J.

Publications and source records attributed to Dean, J..

3 recordsLinked to original sources

bioRxiv2018

Differential role of prefrontal and parietal cortices in controlling level of consciousness

There is current controversy regarding the role of prefrontal versus posterior cortices in consciousness. Clinical and correlative data have been used both to support and refute a causal role for prefrontal cortex in the level of consciousness, but a definitive relationship has not been demonstrated. We used anesthetic-induced unconsciousness as a model system to study the effect of cholinergic and noradrenergic stimulation of rat prefrontal and posterior parietal cortices on the level of consciousness. We demonstrate that cholinergic stimulation of prefrontal cortex, but not parietal cortical areas, restored wakefulness in rats despite continuous exposure to sevoflurane anesthesia. Noradrenergic stimulation of the prefrontal or parietal areas did not reverse the anesthetized state. We conclude that cholinergic mechanisms in prefrontal cortex can control the level of consciousness.\n\nOne Sentence SummaryPrefrontal cholinergic stimulation restores consciousness in rats despite continuous exposure to sevoflurane anesthesia

neuroscience↗

bioRxiv2017

Autosomal recessive coding variants explain only a small proportion of undiagnosed developmental disorders in the British Isles

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.

genetics↗

bioRxiv2017

A mutation in the LMOD1 actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections

We describe a mutation in LMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) in LMOD1 is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family. LMOD1 was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of [~]2% in our study group. Assessment of LMOD1 in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.\n\nValidation of LMOD1 was undertaken using a zebrafish animal model. Knock-down of both lmod1a and lmod1b paralogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the human LMOD1 c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause.\n\nMutations found in the WH2 actin-binding domain of LMOD1 may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.

genetics↗