Mutation screening of the <i>KIF5A</i> gene in Chinese patients with amyotrophic lateral sclerosis

Gu, Xiaojing; Li, Chunyu; Chen, Yongping; Wei, Qianqian; Cao, Bei; Ou, Ruwei; Yuan, Xianglei; Hou, Yanbing; Zhang, Lingyu; Liu, Hui; Wu, Ying; Song, Wei; Zhao, Bi; Chen, Xueping; Shang, Huifang

doi:10.1136/jnnp-2018-318395

Cited by 9 publications

(4 citation statements)

References 6 publications

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“…KIF5A is a protein expressed specifically in neurons and is involved in regulating neuronal microtubule dynamics [ 138 , 139 ]. KIF5A is also associated with spastic paraplegia and Charcot–Marie–Tooth neuropathy [ 140 ] and mutations have been reported in ALS patients in Chinese [ 141 ], European [ 142 , 143 ], and US cohorts [ 137 ].…”

Section: Genetics Of Alsmentioning

confidence: 99%

A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

Connolly

Gall

McCluskey

et al. 2020

JPM

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Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease’s genotype–phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.

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Section: Genetics Of Alsmentioning

confidence: 99%

A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

Connolly

Gall

McCluskey

et al. 2020

JPM

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“…KIF5A mutations are considered a susceptibility factor for ALS [ 4 , 5 ]. KIF5A mutations have been reported to account for 0.16–0.41% of sporadic ALS patients within the Chinese population [ 34 , 35 , 36 ]. In a separate study conducted by Naruse H et al, WES analysis was conducted on a cohort of Japanese patients.…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis

Wang,

Guan,

et al. 2024

Genes

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype–phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.

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“…KIF1A and KIF5A are KIFs that function as molecular motors, utilizing chemical energy from ATPs to transport cargo along microtubules. Studies have indicated that the mutation frequency of KIF5A in the Chinese sALS population ranges from 0.16% (1/645) ( Zhang et al, 2019 ) to 0.41% (2/581) ( Gu et al, 2019 ; He et al, 2020 ). In the Western population, the mutation frequency of KIF5A is reported to be 0.47–0.53% ( Brenner et al, 2018 ; Nicolas et al, 2018 ), which is greater than that in the Chinese population.…”

Section: Discussionmentioning

confidence: 99%

Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing

Zheng,

He,

Chen

et al. 2024

Front. Aging Neurosci.

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ObjectivesGenetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS.MethodsThe analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis.ResultsIn our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations.ConclusionOur investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.

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Mutation screening of the KIF5A gene in Chinese patients with amyotrophic lateral sclerosis

Cited by 9 publications

References 6 publications

A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis

Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing

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