Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the <i>KIF1A</i> gene

Krenn, Martin; Zulehner, Gudrun; Hotzy, Christoph; Rath, Jakob; Stögmann, Elisabeth; Wagner, Matias; Haack, Tobias B.; Strom, Tim M.; Zimprich, Alexander; Zimprich, Fritz

doi:10.1111/ene.13279

Cited by 25 publications

(14 citation statements)

References 19 publications

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“…10,11,18 Interestingly, a recent case report showed that (compound heterozygous) mutations outside of the motor domain can also cause a severe complex phenotype of HSP. 19 We also found that patients with familial mutations were less severely affected. We, however, believe that it is conceivable that severely affected patients are less likely to have progeny, and these mutations are not passed on.…”

Section: Discussionmentioning

confidence: 54%

Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene

et al. 2019

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Several de novo variants in the KIF1A gene have been reported to cause a complicated form of hereditary spastic paraplegia. Additional symptoms include cognitive impairment and varying degrees of peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We describe four patients (ages 10–18 years), focusing on their mobility and gait characteristics. Two patients were not able to walk without assistance and showed a severe abnormal gait pattern, crouch gait. At examination, severe contractures were found.In addition to describing the different phenotypes with specific attention to gait in our cases, we reviewed known KIF1A mutations and summarized their associated phenotypes.We conclude that mobility and cognition are severely affected in children with spastic paraplegia due to de novo KIF1A mutations. Deterioration in mobility is most likely due to progressive spasticity, muscle weakness, and the secondary development of severe contractures, possibly combined with an additional progressive polyneuropathy. Close follow-up and treatment of these patients are warranted.

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Section: Discussionmentioning

confidence: 54%

Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene

et al. 2019

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“…In addition, LIN-2 (CASK) was reported as a regulator of KIF1A clustering and motility in neurons (Wu et al, 2016 ). In recent years, KIF1A has been more widely investigated in the nervous system (Ohba et al, 2015 ; Hung and Coleman, 2016 ; Tanaka et al, 2016 ; Krenn et al, 2017 ). In 2016, we found 19 reports that included KIF1A, and most involved studying neurons.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats

Wang

Zhai

et al. 2018

Front. Cell. Neurosci.

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Binding of extracellular netrin-1 to its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H2 (UNC5H2), inhibits apoptosis mediated by these receptors. A neuron-specific kinesin motor protein, KIF1A, has been shown to participate in netrin-1 secretion. This study aimed to identify the roles of netrin-1 and KIF1A in secondary brain injury after intracerebral hemorrhage (ICH) and the potential mechanisms. An autologous blood ICH model was established in adult male Sprague-Dawley rats, and cultured neurons were exposed to OxyHb to mimic ICH conditions in vitro. Mouse recombinant netrin-1, expression vectors encoding KIF1A, and KIF1A-specific siRNAs were administered intracerebroventricularly. After ICH, protein levels of netrin-1, DCC, and UNC5H2 increased, while protein levels of KIF1A decreased. Levels of UNC5H2 and DCC bound to netrin-1 increased after ICH but were significantly lower than the increase in total amount of protein. Administration of recombinant netrin-1 attenuated neuronal apoptosis and degeneration in ICH rats. Moreover, KIF1A overexpression increased concentrations of netrin-1 in cerebrospinal fluid and cell culture supernatant and exerted neuroprotective effects via netrin-1 and its receptor pathways. KIF1A plays a critical role in netrin-1 secretion by neurons. An increase in protein levels of netrin-1 may be a neuroprotective strategy after ICH. However, this process is almost completely abolished by ICH-induced loss of KIF1A. An exogenous increase of KIF1A may be a potential strategy for neuroprotection via the netrin-1 pathway.

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“…Pathogenic variants in KIF1A were initially associated with autosomal recessive hereditary sensory neuropathy type IIC (HSNIIC; MIM# 614213), autosomal recessive hereditary spastic paraplegia 30 (SPG30; MIM# 610357), and autosomal dominant non‐syndromic intellectual disability 9 (MRD9; MIM# 614255; Erlich et al, 2011; Esmaeeli Nieh et al, 2015; Hotchkiss et al, 2016; Klebe et al, 2012; Krenn et al, 2017; Riviere et al, 2011). HSNIIC‐affected individuals have progressive degeneration of sensory neurons, resulting in loss of feeling in extremities, ulceration, and ultimately amputation of fingers and toes (Riviere et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

et al. 2020

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Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron‐specific ATP‐dependent anterograde axonal transporter of synaptic cargo, are well‐recognized to cause a spectrum of neurological conditions, commonly known as KIF1A‐associated neurological disorders (KAND). Here, we report one mutation‐negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH‐SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.

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Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene

Abstract: This report provides the first evidence that mutations outside the motor domain of the gene can cause (recessive) SPG30 and extends the genotype-phenotype association for KIF1A-related diseases.

Cited by 25 publications

References 19 publications

Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene

Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene

Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

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