期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 96, 期 4, 页码 675-681出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2015.02.012
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资金
- Myelin Disorders Bioregistry Project
- Delman Fund for Pediatric Neurology Education
- NIH National Center for Advancing Translational Sciences [UL1TR000075]
- National Institute of General Medical Sciences [GM110184]
- NIH Cellular and Molecular Biology Training Grant [T32 GM007315]
- Tolz Foundation for Research
- Keystone Innovation Network
- NIH Medical Scientist Training Grant [T32 GM007863]
- NIH [F30 NS092238]
- Australian Research Council
- National Health and Medical Research Council, Australia [APP1068278]
- University of Queensland Foundation Research Excellence Award
- NIH Undiagnosed Diseases Program [LD_0115.0A, LD_0115.0B]
Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations.
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