2. Academic Validation
  3. Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation

Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation

  • Am J Hum Genet. 2018 Jan 4;102(1):188-195. doi: 10.1016/j.ajhg.2017.12.009.
Bobby G Ng 1,  Gege Xu 2,  Nandini Chandy 3,  Joan Steyermark 4,  Deepali N Shinde 5,  Kelly Radtke 5,  Kimiyo Raymond 6,  Carlito B Lebrilla 2,  Ali AlAsmari 7,  Sharon F Suchy 8,  Zöe Powis 5,  Eissa Ali Faqeih 7,  Susan A Berry 4,  David F Kronn 3,  Hudson H Freeze 9
Affiliations

Affiliations

  • 1 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 2 Department of Chemistry, College of Letters and Sciences, University of California, Davis, Davis, CA 95616, USA.
  • 3 Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.
  • 4 Departments of Pediatrics and Genetics, Cell Biology & Development, University of Minnesota, MN 55455, USA.
  • 5 Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 6 Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 7 Section of Medical genetics, Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 8 GeneDx, Gaithersburg, MD 20877, USA.
  • 9 Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
PMID: 29304374 DOI: 10.1016/j.ajhg.2017.12.009
Abstract

Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8. The first individual (consanguineous family) was homozygous for c.715C>T (p.Arg239∗), while the second (non-consanguineous family) was compound heterozygous for c.1009C>G (p.Arg337Gly) and a splice site variant c.1259+5G>T. The third individual (consanguineous family) was homozygous for a c.943C>T (p.Arg315∗). Splicing analysis confirmed the c.1259+5G>T resulted in expression of an abnormal FUT8 transcript lacking exon 9. Functional studies using primary fibroblasts from two affected individuals revealed a complete lack of FUT8 protein expression that ultimately resulted in substantial deficiencies in total core fucosylated N-glycans. Furthermore, serum samples from all three individuals showed a complete loss of core fucosylation. Here, we show that loss of function mutations in FUT8 cause a congenital disorder of glycosylation (FUT8-CDG) characterized by defective core fucosylation that phenotypically parallels some aspects of the Fut8-/- knockout mouse. Importantly, identification of additional affected individuals can be easily achieved through analysis of core fucosylation of N-glycans.

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