KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction
Corresponding Author
Jessica Duis MD, MS
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Address correspondence to Dr. Jessica Duis, McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21287. E-mail: [email protected]Search for more papers by this authorShannon Dean MD, PhD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorCarolyn Applegate MGC, CGC
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorAmy Harper MD
Carolinas Pediatric Neurology Care, Charlotte, NC
Search for more papers by this authorRui Xiao PhD
Department of Molecular and Human Genetics, Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX
Search for more papers by this authorWeimin He PhD
Department of Molecular and Human Genetics, Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX
Search for more papers by this authorLisa R. Sun MD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorMarta Biderman Waberski MD
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
Search for more papers by this authorThomas O. Crawford MD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorAda Hamosh MD, MPH
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorCarl E. Stafstrom MD, PhD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorCorresponding Author
Jessica Duis MD, MS
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Address correspondence to Dr. Jessica Duis, McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD 21287. E-mail: [email protected]Search for more papers by this authorShannon Dean MD, PhD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorCarolyn Applegate MGC, CGC
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorAmy Harper MD
Carolinas Pediatric Neurology Care, Charlotte, NC
Search for more papers by this authorRui Xiao PhD
Department of Molecular and Human Genetics, Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX
Search for more papers by this authorWeimin He PhD
Department of Molecular and Human Genetics, Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX
Search for more papers by this authorLisa R. Sun MD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorMarta Biderman Waberski MD
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
Search for more papers by this authorThomas O. Crawford MD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorAda Hamosh MD, MPH
McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorCarl E. Stafstrom MD, PhD
Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, MD
Search for more papers by this authorThis article was published online on 24 August 2016. After online publication, spacing was revised in Table 1. This notice is included in the online and print versions to indicate that both have been corrected on 09 September 2016.
Abstract
Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin “motor.” These results highlight the role of expanded testing and whole-exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. Ann Neurol 2016;80:633–637
References
- 1Fichera M, Lo Giudice M, Falco M, et al. Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. Neurology 2004; 63: 1108–1110.
- 2Kawaguchi K. Role of kinesin-1 in the pathogenesis of SPG10, a rare form of hereditary spastic paraplegia. Neuroscientist 2013; 19: 336–344.
- 3Liu YT, Laura M, Hersheson J, et al. Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology 2014; 83: 612–619.
- 4Hirokawa N, Noda Y, Tanaka Y, Niwa S. Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 2009; 10: 682–696.
- 5Xia CH, Roberts EA, Her LS, et al. Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J Cell Biol 2003; 161: 55–66.
- 6Nakajima K, Yin X, Takei Y, et al. Molecular motor KIF5A is essential for GABA(A) receptor transport, and KIF5A deletion causes epilepsy. Neuron 2012; 76: 945–961.
- 7Karle KN, Mockel D, Reid E, Schols L. Axonal transport deficit in a KIF5A(-/-) mouse model. Neurogenetics 2012; 13: 169–179.
- 8Harel T, Yesil G, Bayram Y, et al. Monoallelic and biallelic variants in EMC1 identified in individuals with global developmental delay, hypotonia, scoliosis, and cerebellar atrophy. Am J Hum Genet 2016; 98: 562–570.
- 9DaRe JT, Vasta V, Penn J, et al. Targeted exome sequencing for mitochondrial disorders reveals high genetic heterogeneity. BMC Med Genet 2013; 14: 118.
- 10Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE. Nonsense-mediated decay approaches the clinic. Nat Genet 2004; 36: 801–808.
- 11Richards S, Aziz N, Bale S et al.; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–424.
- 12Faheem M, Chaudhary AG, Kumosani TA, et al. Interaction of different proteins with GABAA receptor and their modulatory effect on inhibitory neural transmission leads to epilepsy. CNS Neurol Disord Drug Targets 2014; 13: 1148–1159.
- 13Twelvetrees AE, Yuen EY, Arancibia-Carcamo IL, et al. Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron 2010; 65: 53–65.
- 14Karle KN, Mockel D, Reid E, Schols L. Axonal transport deficit in a KIF5A(-/-) mouse model. Neurogenetics 2012; 13: 169–179.
- 15Fuger P, Sreekumar V, Schule R, et al. Spastic paraplegia mutation N256S in the neuronal microtubule motor KIF5A disrupts axonal transport in a Drosophila HSP model. PLoS Genet 2012; 8: e1003066.
- 16Campbell PD, Shen K, Sapio MR, et al. Unique function of kinesin KIF5A in localization of mitochondria in axons. J Neurosci 2014; 34: 14717–14732.
- 17Schwarz TL. Mitochondrial trafficking in neurons. Cold Spring Harb Perspect Biol 2013; 5(6). pii: a011304. doi: 10.1101/cshperspect.a011304.
- 18Iworima DG, Pasqualotto BA, Rintoul GL. Kif5 regulates mitochondrial movement, morphology, function and neuronal survival. Mol Cell Neurosci 2016; 72: 22–33.
Citing Literature
