To date, 45 KIF genes grouped into 15 families have been identified (it is even estimated that there are twice as many proteins!). Kinesine superfamily (KIF) genes code for motor proteins that play a fundamental role in the functioning, development, survival and plasticity of the brain.

The KIF5C gene, located on chromosome 2, contains information that will make protein from the kinesine family. These proteins play a major role in the transport of molecules within the central nervous system.

The mutation in this KIF5C gene results in a change in genetic information, resulting in brain malformation and dysfunction associated with the KIF5C gene mutation.

Involvement of kinesine family members KIF4A and KIF5C in intellectual disability and synaptic function.

Introduction

Kinesine superfamily genes (KIF) code for motor proteins that play a fundamental role in the functioning, development, survival and plasticity of the brain by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Knock-out studies in mice support these important nervous system functions. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes interfere with synaptic function.

Method

Applying new generation sequencing (NGS) in ID patients, we identified probable pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we conducted functional studies of synaptic function in primary rat hippocampal neurons.

Results and conclusions

Four males from the same family with a disruptive mutation in the KIF4A bound to the X showed mild to moderate DI and epilepsy. A patient with novo false-sense mutation in KIF5C had severe ID, epilepsy, microcephaly, and cortical malformation. KIFA4 inactivation in primary rat hippocampus neurons altered the balance between excitatory and inhibitory synaptic transmission, while Kif5c mutation affected its protein function in excitatory synapses. Our results suggest that KIF4A and KIF5C mutations cause ID by tilting the balance between excitatory and inhibitory synaptic excitability.

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Link to the complete study : National Library of Medicine

KIF5C mutations cause a neurodevelopmental disorder of childhood epilepsy, a lack of language and distinctive malformations of cortical development.

Introduction

With the advent of new generation sequencing methods (NGS), an increasing number of genes are identified in association with a wide range of complex brain development disorders (Barkovich et al. 2012). The diagnosis of severe cortical malformations, such as classical smoothencephaly, is often clinically feasible by identifying abnormalities characteristic of neuroimaging, which facilitates a more targeted molecular test strategy (Guerrini and Dobyns 2014). However, more complex cortical malformations continue to pose diagnostic challenges due to the variability of neuroimaging characteristics of brain malformation and/or the scarcity of individual types of malformations. Examples of such malformations include polymicrogyria (PMG), variable types of pachygyria, and more subtle forms of cortical dysplasia. The KIF5C gene was recently identified in 2013 as a rare cause of cortical malformations variablely characterized by regional or focal pachygyria with or without microcephaly, with only four children identified as having mutations in this gene, to date (Jamuar et al. 2014 ; Poirier et al., 2013 ; Willemsen et al., 2014 ; Cavallin et al. 2016). Here we report two children with cerebral malformations, childhood epilepsy and neurodevelopmental problems due to the same novo KIF5C mutation. By adding our patients to the four previously reported individuals, we show that mutations in

Equipment and methodology

Patients were enrolled in the Seattle Children's Research Institute's developmental brain disorder research program, with approval from the BRI. The researchers examined all clinical, neuroimaging and molecular data. Molecular analysis was performed using new-generation, clinically available, targeted commercial panels composed of > 1000 genes associated with epilepsy, intellectual impairment and autism using the Exome d'Agilent Clinical Research kit. Sequencing was performed using the Illumina sequencing system with 2×100 bp paired end readings.

Results

The neuroimaging and clinical characteristics of our two patients, as well as individuals carrying the previously published KIF5C mutation, are summarized in Table 1.

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Link to the complete study : National Library of Medicine

Expansion of the molecular and clinical phenotype of patients with novo variants in KIF5C : a series of six patients.

Introduction

Heterozygous de novo variants of loss of function in the motor domain of KIF5C are associated with a neurodevelopmental disorder characterized by infantile epilepsy, frontal cortical dysplasia and developmental delays, including motor and speech disorders. Previously, only three false-sense variants of KIF5C were known to be pathogenic. We identified six other patients with significant developmental delays with de novo heterozygous variants of the KIF5C gene (Glu237Val, Thr93Ile, Thr93Asn, Ser90del, Lys92Arg and Glu237Lys), four of which had not been previously reported. Functional evaluation was performed on fluorescence-labelled KIF5C variants expressed in isolated neurons of the hippocampus. Novo pathogenic variants showed significantly reduced motor function compared to wild type KIF5C. We conclude that the presented de novo pathogens have reduced motor activity and that it is likely to be the etiology of patient symptoms given the strain of the gene in the population. By adding these patients to the seven previously reported patients, we are able to broaden the phenotypic spectrum associated with the pathogenic variants of KIF5C. The evaluation of the neurodevelopmental phenotype of other individuals with variants of loss of function in KIF5C is indicated to further characterize the spectrum of associated phenotypes.

The kinesine protein superfamily (KIF) acts as ATP-dependent molecular motors to facilitate intracellular transport along microtubules (Hirokawa et al. 2009), a process essential to brain development, functioning, plasticity and survival (Hirokawa, Niwa and Tanaka 2010). KIF proteins regulate the transport of cargoes such as vesicles, organelles, protein complexes, mRNAs, and chromosomes along microtubules within axons, dendrites, and synapses (Willemsen et al. 2014). KIF proteins are regulated by phosphorylation. For example, c-Jun NH2-terminal kinase 3 (JNK3) phosphoryles the engine domain of KIF5C (one of the three variants also known as kinesine-1 (Miki et al. 2001)), preventing KIF5C from binding to microtubules (Morfini et al. 2009). Disruption of the normal phosphorylation process of KIF5C proteins was suspected as a physiopathological mechanism for neurodegenerative diseases. Abnormally long repeats of polyglutamine in the pathogenic form of huntingtin increased the activity of JNK3, causing hyperphosphorylation of KIF5C, suggesting that the pathology of Huntington's disease may in part result from reduced cargo transport along microtubules by KIF5 proteins (Morfini et al. 2009).

Similarly, genetic variants that directly disrupt the functioning of the motor domain also produce neurological phenotypes (Duquesne et al. 2020; Naim et al., 2022; Banerjee et al., 2024; Becker et al., 2024). It has been established that the KIF5C gene is the genetic cause of a neurodevelopmental disorder characterized by childhood epilepsy, frontal cortical dysplasia and developmental delays, including motor and speech disorders, with seven patients reported in the literature to date (Willemsen et al., 2014; Duquesne et al., 2020; Jamuar et al., 2014; Poirier et al., 2013; Cavallin et al., 2016; Michels et al., 2017). Neurodevelopmental disorder is the result of KIF5C coded kinesin proteins that host a non-functional motor domain and lose the ability to bind to hydrolyzed ATP (Padzik et al. 2016), which alters or inhibits the transport of cargo mediated by KIF5C along microtubules. It is interesting to note that five of the seven patients reported had variants involving Glu237 amino acid, four of which shared the same false-sense variant, p.Glu237Lys, suggesting a hot spot for variants and potential genotype-phenotype correlations (Michels et al. 2017).

To date, only three false-sense variants of KIF5C have been reported (Willemsen et al. 2014; Jamuar et al., 2014; Poirier et al., 2013; Cavallin et al., 2016; Michels et al., 2017). The KIF5C gene was first identified as the cause of cortical development malformation (Poirier et al. 2013). People affected generally have neurodevelopmental retardation, childhood epilepsy, intellectual impairment and psychomotor retardation and behavioural problems (Duquesne et al. 2020; Banerjee et al., 2024; Michels et al., 2017). Malformation of cortical development may include polymicrogyria and pachygyria and cerebral atrophy (Duquesne et al. 2020; Banerjee et al., 2024; Michels et al., 2017). However, clinical signs such as epilepsy, developmental delays and intellectual impairments are common clinical presentations for a wide variety of genetic and multifactorial conditions and therefore do not immediately suggest an underlying etiology of KIF5C. The increasing use of new generation sequencing technologies (NGS) in the diagnostic assessment of these children leads to the discovery of variants of uncertain significance in KIF5C. Here we report six other children with de novo variants in KIF5C, four of which have never been reported before. By adding these patients to the seven previously reported patients, the phenotypic spectrum associated with the pathogenic variants of KIF5C is expanded.

Method

This series of cases was prepared on the basis of protocol #19-0751 of the Colorado Multiple Institutional Review Board (COMIRB).

Results and conclusions

Four males from the same family with a disruptive mutation in the KIF4A bound to the X showed mild to moderate DI and epilepsy. A patient with novo false-sense mutation in KIF5C had severe ID, epilepsy, microcephaly, and cortical malformation. KIFA4 inactivation in primary rat hippocampus neurons altered the balance between excitatory and inhibitory synaptic transmission, while Kif5c mutation affected its protein function in excitatory synapses. Our results suggest that KIF4A and KIF5C mutations cause ID by tilting the balance between excitatory and inhibitory synaptic excitability.

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Link to the complete study : Wiley Online Library

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