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Am J Hum Genet. 2018 Dec 6;103(6):1030-1037. doi: 10.1016/j.ajhg.2018.10.021. Epub 2018 Nov 29.

Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation.

Author information

1
Human Genetics Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Neurology Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
5
Department of Neurology, University of Rochester School of Medicine, Rochester, NY 14623, USA.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
7
Human Genetics Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: hudson@sbpdiscovery.org.

Abstract

FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway.

KEYWORDS:

congenital disorder of glycosylation; encephalopathy; fucosylation; glycan, fucose; intellectual disability; salvage

PMID:
30503518
DOI:
10.1016/j.ajhg.2018.10.021

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