Abstract
Spondylo-epi-metaphyseal dysplasia (SEMD) is a group of inherited skeletal diseases characterized by the anomalies in spine, epiphyses and metaphyses. SEMD is highly heterogeneous and >20 distinct entities have been identified. Here we describe a novel type of SEMD in two unrelated Turkish patients who presented with severe platyspondyly, kyphoscoliosis, pelvic distortion, constriction of the proximal femora and brachydactyly. Although these phenotypes overlap considerably with some known SEMDs, they had a novel causal gene, exostosin-like glycosyltransferase 3 (EXTL3), that encodes a glycosyltransferase involved in the synthesis of heparin and heparan sulfate. The EXTL3 mutation identified in the patients was a homozygous missense mutation (c.953C>T) that caused a substitution in a highly conserved amino acid (p.P318L). The enzyme activity of the mutant EXTL3 protein was significantly decreased compared to the wild-type protein. Both patients had spinal cord compression at the cranio-vertebral junction and multiple liver cysts since early infancy. One of the patients showed severe immunodeficiency, which is considered non-fortuitous association. Our findings would help define a novel type of SEMD caused by EXTL3 mutations.
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Acknowledgements
We thank the patients and their families for their help to the study. This study was supported in part by research grants from Japan Agency For Medical Research and Development (AMED; contract No 14525125), by a Grant-in-Aid for Scientific Research (C) 16K08251 (to SM) from the Japan Society for the Promotion of Science, Japan, and by the Nakatomi Foundation (to SM).
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Guo, L., Elcioglu, N., Mizumoto, S. et al. Identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-metaphyseal dysplasia. J Hum Genet 62, 797–801 (2017). https://doi.org/10.1038/jhg.2017.38
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DOI: https://doi.org/10.1038/jhg.2017.38
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