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Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene
- Source :
- Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017), Scientific Reports, SCIENTIFIC REPORTS(7)
- Publication Year :
- 2017
- Publisher :
- Nature Portfolio, 2017.
-
Abstract
- KIF1A is a brain-specific anterograde motor protein that transports cargoes towards the plus-ends of microtubules. Many variants of the KIF1A gene have been associated with neurodegenerative diseases and developmental delay. Homozygous mutations of KIF1A have been identified in a recessive subtype of hereditary spastic paraplegia (HSP), SPG30. In addition, KIF1A mutations have been found in pure HSP with autosomal dominant inheritance. Here we report the first case of familial complicated HSP with a KIF1A mutation transmitted in autosomal dominant inheritance. A heterozygous p.T258M mutation in KIF1A was found in a Korean family through targeted exome sequencing. They displayed phenotypes of mild intellectual disability with language delay, epilepsy, optic nerve atrophy, thinning of corpus callosum, periventricular white matter lesion, and microcephaly. A structural modeling revealed that the p.T258M mutation disrupted the binding of KIF1A motor domain to microtubules and its movement along microtubules. Assays of peripheral accumulation and proximal distribution of KIF1A motor indicated that the KIF1A motor domain with p.T258M mutation has reduced motor activity and exerts a dominant negative effect on wild-type KIF1A. These results suggest that the p.T258M mutation suppresses KIF1A motor activity and induces complicated HSP accompanying intellectual disability transmitted in autosomal dominant inheritance.
- Subjects :
- 0301 basic medicine
Adult
Male
Microcephaly
Adolescent
Hereditary spastic paraplegia
Science
Kinesins
Dominant-Negative Mutation
Biology
Corpus callosum
Microtubules
Article
03 medical and health sciences
Young Adult
0302 clinical medicine
Intellectual Disability
medicine
Humans
Genetic Predisposition to Disease
Language Development Disorders
Child
Exome sequencing
KIF1A
Genetics
Multidisciplinary
Spastic Paraplegia, Hereditary
Neurodegeneration
Brain
Infant
medicine.disease
Pedigree
030104 developmental biology
Organ Specificity
Child, Preschool
Mutation (genetic algorithm)
Mutation
Medicine
Female
030217 neurology & neurosurgery
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....232fcbae1f76952f197649e123bb908f