Biology subjects

Kok, F.

Publications and source records attributed to Kok, F..

4 recordsLinked to original sources

bioRxiv2023

Bi-allelic variants in WDR47 lead to neuronal loss causing a rare neurodevelopmental syndrome with corpus callosum dysgenesis in humans.

The corpus callosum (CC) is the largest interhemispheric connection that is largely formed by the axons of layer 2/3 callosal projection neurons (CPNs) through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps may prevent the proper development of the corpus callosum resulting in a spectrum of disorders collectively referred to as corpus callosum dysgenesis (CCD). Here, we report four unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly, cerebellar abnormalities and hydrocephalus. Using a combination of in vitro and in vivo mouse models and complementation assays, we show that independently from its previously identified functions in neuronal migration and axonal extension, WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further provide evidence that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.

neuroscience↗

bioRxiv2021

Heterogeneous pdgfrβ+ cells regulate coronary vessel development and revascularization during heart regeneration

Endothelial cells emerge from the atrioventricular canal (AVC) to form nascent coronary blood vessels in the juvenile zebrafish heart. We found that pdgfr{beta} is first expressed in the epicardium around the AVC and later becomes localized mainly in the mural cells. pdgfr{beta} mutant fish display severe defects in mural cell recruitment and coronary vessel development. pdgfr{beta}+ mural cells are heterogeneous and those associated with coronary arteries also express cxcl12b. Mural cells positive for both pdgfr{beta} and cxcl12b transgenic reporters had elevated expression of smooth muscle cell genes. Interestingly, these mural cells were associated with coronary arteries even in the absence of Pdgfr{beta}, although smooth muscle gene expression was downregulated in these cells. We found that pdgfr{beta} expression dynamically changes in the epicardium derived cells, which we found to be a heterogeneous population. mdka was identified as a gene upregulated in subpopulations of pdgfr{beta}+ cells during heart regeneration. However, pdgfr{beta} but not mdka mutants showed defects in heart regeneration. Our results demonstrated that pdgfr{beta}+ cells and Pdgfr{beta} signaling are essential for coronary development and heart regeneration. SUMMARY STATEMENTHeterogeneous pdgfr{beta} positive cells are present in developing and regenerating zebrafish hearts and are required for development of mural cells and their association with the nascent coronary vessels during zebrafish heart development and regeneration.

developmental biology↗

bioRxiv2020

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

genetics↗

bioRxiv2019

Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 individuals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 individuals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the individuals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

genetics↗