Abstract
The diphthamide biosynthesis 1 (DPH1) gene encodes one of the essential components of the enzyme catalyzing the first step of diphthamide formation on eukaryotic elongation factor 2 (EEF2). Diphthamide is the posttranslationally modified histidine residue on EEF2 that promotes protein chain elongation in the ribosome. DPH1 defects result in a failure of protein synthesis involving EEF2, leading to growth defects, embryonic lethality, and cell death. In humans, DPH1 mutations cause developmental delay with a short stature, dysmorphic features, and sparse hair, and are inherited in an autosomal recessive manner (MIM#616901). To date, only two homozygous missense mutations in DPH1 (c.17T>A, p.Met6Lys and c.701T>C, p.Leu234Pro) have been reported. We used WES to identify novel compound heterozygous mutations in DPH1 (c.289delG, p.Glu97Lysfs*8 and c.491T>C, p.Leu164Pro) in a patient from a nonconsanguineous family presenting with intellectual disability, a short stature, craniofacial abnormalities, and external genital abnormalities. The clinical phenotype of all patients with DPH1 mutations, including the current patient, revealed core features, although the external genital anomaly was newly recognized in our case.
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Acknowledgements
The authors thank the patient and his family for participating in this work. This study was supported by grants from: Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science; Initiative on Rare and Undiagnosed Diseases in Pediatrics and Initiative on Rare and Undiagnosed Diseases for Adults from the Japan Agency for Medical Research and Development; Grants-in-Aid for Scientific Research (A and B) from the Japan Society for the Promotion of Science; Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; grants from the Ministry of Health, Labour and Welfare; the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists. We thank Sarah Williams, PhD, from Edanz Group (www.edanzediting.com) for editing a draft of this manuscript.
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Nakajima, J., Oana, S., Sakaguchi, T. et al. Novel compound heterozygous DPH1 mutations in a patient with the unique clinical features of airway obstruction and external genital abnormalities. J Hum Genet 63, 529–532 (2018). https://doi.org/10.1038/s10038-017-0399-2
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DOI: https://doi.org/10.1038/s10038-017-0399-2
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