Biology subjects

Gurnett, C. A.

Publications and source records attributed to Gurnett, C. A..

3 recordsLinked to original sources

bioRxiv2025

Replicable, Transdiagnostic Behavioral and Neural Correlates of Sensory Over-responsivity

ObjectiveSensory over-responsivity (SOR), characterized by strong negative reactions to typically innocuous stimuli, is considered a symptom of autism spectrum disorder. However, SOR also affects 15-20% of children overall, including a majority of children with common psychiatric conditions. Despite its prevalence, the clinical specificity and neurobiological bases of SOR remain poorly understood. Our study aims to determine the specific clinical significance of SOR across diverse child samples and establish whether SOR is associated with replicable patterns of functional connectivity (FC). MethodWe analyzed data from 15,728 children (ages 6-17.9 years) across five datasets: three community samples, including the Adolescent Brain Cognitive Development [ABCD] and Healthy Brain Network [HBN] studies, and two autism-enriched samples. Bivariate and multivariate models examined associations between SOR and symptoms of anxiety, attention-deficit/hyperactivity disorder, depression, conduct disorder, and oppositional defiant disorder, as well as autistic traits. Analysis of resting-state functional MRI (fMRI) data from the ABCD study (n=4195) identified candidate brain-wide and circuit-specific FC correlates of mild SOR and tested replication of effects in an independent ABCD subsample (n=4190). Additional analyses tested extension to children with severe SOR in ABCD and replication in smaller samples [HBN (n=356), ABCD subset (n=356)]. ResultsMultivariate analyses revealed that SOR is associated with a remarkably consistent profile across samples: greater levels of both autistic traits and anxiety symptoms and, in community samples, lower levels of conduct disorder symptoms. Across samples, SOR is not reliably associated with symptoms of any other analyzed psychiatric conditions. Mild SOR is associated with brain-wide FC patterns and, specifically, reduced FC between cingulo-parietal network and bilateral caudate nucleus; these patterns show robust replication across independent ABCD subsamples and extension to severe SOR in ABCD but are not significant in smaller samples, indicating that large sample size is needed to reliably detect brain effects. ConclusionResults suggest that SOR may constitute a latent trait associated with both specific clinical risk and protection, and with replicable cortico-subcortical neural correlates. These findings advance our understanding of the neurobiology and clinical relevance of SOR. They may also inform clinical practice and future research aimed at understanding and supporting individuals with sensory challenges.

neuroscience↗

bioRxiv2024

Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle

Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C). Whereas skeletal muscle isoforms of MyBP-C (fMyBP-C, sMyBP-C) modulate muscle contractility via interactions with actin thin filaments and myosin motors within the muscle sarcomere "C-zone," MyBP-H has no known function. This is in part due to MyBP-H having limited expression in adult fast-twitch muscle and no known involvement in muscle disease. Quantitative proteomics reported here reveal MyBP-H is highly expressed in prenatal rat fast-twitch muscles and larval zebrafish, suggesting a conserved role in muscle development, and promoting studies to define its function. We take advantage of the genetic control of the zebrafish model and a combination of structural, functional, and biophysical techniques to interrogate the role of MyBP-H. Transgenic, FLAG-tagged MyBP-H or fMyBP-C both localize to the C-zones in larval myofibers, whereas genetic depletion of endogenous MyBP-H or fMyBP-C leads to increased accumulation of the other, suggesting competition for C-zone binding sites. Does MyBP-H modulate contractility from the C-zone? Globular domains critical to MyBP-Cs modulatory functions are absent from MyBP-H, suggesting MyBP-H may be functionally silent. However, our results suggest an active role. Small angle x-ray diffraction of intact larval tails revealed MyBP-H contributes to the compression of the myofilament lattice accompanying stretch or contraction, while in vitro motility experiments indicate MyBP-H shares MyBP-Cs capacity as a molecular "brake". These results provide new insights and raise questions about the role of the C-zone during muscle development.

biophysics↗

bioRxiv2018

Mutations in Kinesin Family Member 6 Reveal Specific Role in Ependymal Cell Function and Human Neuro-Cranial Development

Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurocranial defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cell (EC) layer of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed a reduction in EC cilia, without effect on other multiciliated tissues. Consistent with our findings in mice, defects of the ventricular system and EC cilia were observed in kif6 mutant zebrafish. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neuro-cranial morphogenesis with a specific role in the maintenance of EC cilia in vertebrates.\n\nAUTHOR SUMMARYCerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain. Localized flows of cerebrospinal fluid throughout the ventricular system of the brain are established from the polarized beating of the ependymal cell (EC) cilia. Here, we identified a homozygous truncating mutation in KIF6 in a child displaying neuro-cranial defects and intellectual disability. To test the function of KIF6 in vivo, we engineered mutations of Kif6 in mouse. These Kif6 mutant mice display severe hydrocephalus, coupled with a loss of EC cilia. Similarly, we observed hydrocephalus and a reduction in EC cilia in kif6 mutant zebrafish. Overall, this work describes the first clinically-defined KIF6 mutation in human, while our animal studies demonstrate the pathogenicity of mutations in KIF6 and establish KIF6 as a conserved mediator of neuro-cranial development and EC cilia maintenance in vertebrates.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC=\"FIGDIR/small/350140_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (58K):\norg.highwire.dtl.DTLVardef@d36bc6org.highwire.dtl.DTLVardef@48cbfborg.highwire.dtl.DTLVardef@147e273org.highwire.dtl.DTLVardef@641ce3_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗