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

Bobby G. Ng, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N. Shinde, Kelly Radtke, Kimiyo Raymond, Carlito B. Lebrilla, Ali AlAsmari, Sharon F. Suchy, Zöe Powis, Eissa Ali Faqeih, Susan A. Berry, David F. Kronn, Hudson H. Freeze

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)188-195
Number of pages8
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2018

Fingerprint

Congenital Disorders of Glycosylation
Fucosyltransferases
Mutation
Polysaccharides
Exome
Fucose
Fetal Growth Retardation
Monosaccharides
Knockout Mice
Exons
Glycoproteins
Extremities
Fibroblasts
Growth
Serum
Proteins

Cite this

Ng, B. G., Xu, G., Chandy, N., Steyermark, J., Shinde, D. N., Radtke, K., ... Freeze, H. H. (2018). Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation. American Journal of Human Genetics, 102(1), 188-195. https://doi.org/10.1016/j.ajhg.2017.12.009

Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation. / Ng, Bobby G.; Xu, Gege; Chandy, Nandini; Steyermark, Joan; Shinde, Deepali N.; Radtke, Kelly; Raymond, Kimiyo; Lebrilla, Carlito B.; AlAsmari, Ali; Suchy, Sharon F.; Powis, Zöe; Faqeih, Eissa Ali; Berry, Susan A.; Kronn, David F.; Freeze, Hudson H.

In: American Journal of Human Genetics, Vol. 102, No. 1, 04.01.2018, p. 188-195.

Research output: Contribution to journalArticle

Ng, BG, Xu, G, Chandy, N, Steyermark, J, Shinde, DN, Radtke, K, Raymond, K, Lebrilla, CB, AlAsmari, A, Suchy, SF, Powis, Z, Faqeih, EA, Berry, SA, Kronn, DF & Freeze, HH 2018, 'Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation', American Journal of Human Genetics, vol. 102, no. 1, pp. 188-195. https://doi.org/10.1016/j.ajhg.2017.12.009
Ng, Bobby G. ; Xu, Gege ; Chandy, Nandini ; Steyermark, Joan ; Shinde, Deepali N. ; Radtke, Kelly ; Raymond, Kimiyo ; Lebrilla, Carlito B. ; AlAsmari, Ali ; Suchy, Sharon F. ; Powis, Zöe ; Faqeih, Eissa Ali ; Berry, Susan A. ; Kronn, David F. ; Freeze, Hudson H. / Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation. In: American Journal of Human Genetics. 2018 ; Vol. 102, No. 1. pp. 188-195.
@article{3b3dfdb8e3174d438221eb30be10b366,
title = "Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation",
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.",
author = "Ng, {Bobby G.} and Gege Xu and Nandini Chandy and Joan Steyermark and Shinde, {Deepali N.} and Kelly Radtke and Kimiyo Raymond and Lebrilla, {Carlito B.} and Ali AlAsmari and Suchy, {Sharon F.} and Z{\"o}e Powis and Faqeih, {Eissa Ali} and Berry, {Susan A.} and Kronn, {David F.} and Freeze, {Hudson H.}",
year = "2018",
month = "1",
day = "4",
doi = "10.1016/j.ajhg.2017.12.009",
language = "English (US)",
volume = "102",
pages = "188--195",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Biallelic Mutations in FUT8 Cause a Congenital Disorder of Glycosylation with Defective Fucosylation

AU - Ng, Bobby G.

AU - Xu, Gege

AU - Chandy, Nandini

AU - Steyermark, Joan

AU - Shinde, Deepali N.

AU - Radtke, Kelly

AU - Raymond, Kimiyo

AU - Lebrilla, Carlito B.

AU - AlAsmari, Ali

AU - Suchy, Sharon F.

AU - Powis, Zöe

AU - Faqeih, Eissa Ali

AU - Berry, Susan A.

AU - Kronn, David F.

AU - Freeze, Hudson H.

PY - 2018/1/4

Y1 - 2018/1/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040588389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040588389&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.12.009

DO - 10.1016/j.ajhg.2017.12.009

M3 - Article

C2 - 29304374

AN - SCOPUS:85040588389

VL - 102

SP - 188

EP - 195

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -