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KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy
Author(s) -
Rydzanicz M.,
Jagła M.,
Kosinska J.,
Tomasik T.,
Sobczak A.,
Pollak A.,
HermanSucharska I.,
Walczak A.,
Kwinta P.,
Płoski R.
Publication year - 2017
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12831
Subject(s) - missense mutation , mutation , biology , signal transducing adaptor protein , hereditary spastic paraplegia , genetics , phenotype , gene
The KIF5A gene ( OMIM 602821) encodes a neuron‐specific kinesin heavy chain involved in intracellular transport of mitochondria and other cargoes. KIF5A protein comprises the N terminal motor domain, the stalk domain and the C‐terminal cargo binding domain. The binding between KIF5A and its cargoes is mediated by kinesin adaptor proteins such as TRAK1 and TRAK2 . Numerous missense KIF5A mutations in the motor and stalk domains cause spastic paraplegia type 10 ( SPG10 , OMIM 604187). Conversely, the role of loss‐of‐function mutations, especially those affecting the cargo binding domain, is unclear. We describe a novel de novo KIF5A p.Ser974fs/c. 2921delC mutation found by whole exome sequencing in a patient with a congenital severe disease characterized by myoclonic seizures and progressive leukoencephalopathy. Since this phenotype differs considerably from the KIF5A / SPG10 disease spectrum we propose that the KIF5A p.Ser974fs and possibly other mutations which lead to truncation of the C‐terminal tail of the protein cause a novel disorder. We speculate that the unique effect of the C‐terminal truncating KIF5A mutations may result from the previously described complex role of this protein domain in binding of the TRAK2 and possibly other kinesin adaptor protein(s).