FUT2 W154X - GET-Evidence

Curation:
Currentness:

FUT2 W154X

(FUT2 Trp154Stop)


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Short summary

This recessive protective variant confers resistance to norovirus (which causes stomach flu). 20% of Caucasians and Africans are homozygous for this variant and are “non-secretors”: they do not express ABO blood type antigens in their saliva or mucosal surfaces. Most strains of norovirus bind to these antigens in the gut, and so this non-secretor status confers almost total resistantance to most types of norovirus. There are notable exceptions, some strains of norovirus bind a different target and are equally infectious for secretors and non-secretors.

Variant evidence
Computational 2

Nonsense mutation

Functional 2

Binding studies find most norovirus strains bind specifically to saliva of secretors, and not non-secretors (Lindesmith 2003). Norovirus binding to glycosphingolipids in particular (in addition to glycoproteins with ABO antigens) (Rydell 2009), these molecules have been shown to be a mechanism for viral entry in other viruses.

See Lindesmith L et al. 2003 (12692541), Rydell GE et al. 2009 (19625485).

Case/Control 4

p=0.00016 from Lindesmith et al.

See Lindesmith L et al. 2003 (12692541), Rydell GE et al. 2011 (22025362).

Familial -
 
Clinical importance
Severity 2

For susceptible individuals, not usually symptomatic — chances of stomach flu infection for susceptible individuals is ~8% per year.

Treatability 3

Hand washing and correct handling of food substantially reduce transmission.

Penetrance 5

Resistant to the majority of norovirus strains. However, some strains are still infectious for non-secretors, see Nordgren et al.

 

Impact

Moderate clinical importance, protective

(The "moderate clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

According to the CDC ( http://www.cdc.gov/ncidod/dvrd/revb/gastro/norovirus-factsheet.htm ), there are an estimated 21 million cases per year of norovirus infection (6-7% of the total population in a given year).

Allele frequency

  • A @ chr19:49206674: 49.1% (5277/10758) in EVS
  • A @ chr19:53898485: 42.2% (54/128) in GET-Evidence
  • Frequency shown in summary reports: 49.1% (5277/10758)

Publications
 

Kelly RJ, Rouquier S, Giorgi D, Lennon GG, Lowe JB. Sequence and expression of a candidate for the human Secretor blood group alpha(1,2)fucosyltransferase gene (FUT2). Homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem. 1995 Mar 3;270(9):4640-9. PubMed PMID: 7876235.

 

Lindesmith L, Moe C, Marionneau S, Ruvoen N, Jiang X, Lindblad L, Stewart P, LePendu J, Baric R. Human susceptibility and resistance to Norwalk virus infection. Nat Med. 2003 May;9(5):548-53. Epub 2003 Apr 14. PubMed PMID: 12692541.

In this volunteer infection study, volunteers were exposed to varying concentrations of norovirus. In addition, secretor vs. non-secretor status was tested via functional and genetic tests. Among the secretors, combining all different doses, 34 out of 55 became infected after exposure. Of the non-secretors, none were infected, regardless of dose (0 out of 22), a p-value of 0.00016 using a two-tailed Fisher’s Exact test.

Norwalk virus-like particles were found to bind only saliva from secretor (Se+) volunteers.

The paper also describes the impact of Norovirus in the US as “an estimated 23,000,000 infections, 50,000 hospitalizations and 300 deaths per year”.

Rydell GE, Dahlin AB, Höök F, Larson G. QCM-D studies of human norovirus VLPs binding to glycosphingolipids in supported lipid bilayers reveal strain-specific characteristics. Glycobiology. 2009 Nov;19(11):1176-84. Epub 2009 Jul 22. PubMed PMID: 19625485.

 

Nordgren J, Kindberg E, Lindgren PE, Matussek A, Svensson L. Norovirus gastroenteritis outbreak with a secretor-independent susceptibility pattern, Sweden. Emerg Infect Dis. 2010 Jan;16(1):81-7. PubMed PMID: 20031047; PubMed Central PMCID: PMC2874438.

 

Edited in this revision:

Rydell GE, Kindberg E, Larson G, Svensson L. Susceptibility to winter vomiting disease: a sweet matter. Rev Med Virol. 2011 Nov;21(6):370-82. doi: 10.1002/rmv.704. Epub 2011 Aug 25. Review. PubMed PMID: 22025362.

A recent review paper compiling various studies regarding norovirus susceptibility and genotypes (secretor status and ABO blood types). These studies are both voluntary infection studies, and cases of natural infections. FUT2, along with FUT1, is responsible for expression of the H antigens — these are what become modified to become A, B, and O types. FUT1 is responsible for expression in red blood cells, while FUT2 is responsible for secretion in mucosal tissues & saliva. This variant (FUT2-W154X) results in “non-secretor” status: individuals homozygous for this do not express the ABO antigens on their mucosal tissues / saliva (but still do on their red blood cells).

In general non-secretors are found to be almost completely resistant to norovirus. Notably, there are reports of some strains where non-secretors are susceptible. Consistent with this, binding studies using virus-like particles find a secretor-dependent binding pattern. These seem to be an exception among norovirus strains, however.

Groups have also reported variable binding to the different ABO in some strains (while other strains do not have such a bias) — for example, blood type B doesn’t seem to be bound by the GI.1 strain (while O, A, and AB are). This may explain why there are some reports of variability in norovirus susceptibility base on ABO type (with O generally more sensitive).

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
hom A @ chr19:49206674

 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het A @ chr19:49206674

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het A @ chr19:49206674

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
hom A @ chr19:49206674

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
hom A @ chr19:49206674

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het A @ chr19:49206674

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het A @ chr19:49206674

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het A @ chr19:49206674

 

 

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
hom A @ chr19:49206674

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het A @ chr19:49206674

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
hom A @ chr19:49206674

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr19:49206674

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het A @ chr19:49206674

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
hom A @ chr19:49206674

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr19:49206674

 

 

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het A @ chr19:49206674

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het A @ chr19:49206674

 

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het A @ chr19:49206674

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het A @ chr19:49206674

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr19:49206674

 

huD81F3D - CGI sample GS01173-DNA_D06 from PGP sample 69488604
hom A @ chr19:49206674

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr19:49206674

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
hom A @ chr19:49206674

 

huFFAD87 - CGI sample GS01669-DNA_H05 from PGP sample 10971581
het A @ chr19:49206674

 

GS06985 - var-GS06985-1100-36-ASM
hom A @ chr19:53898486

 

GS06994 - var-GS06994-1100-36-ASM
het A @ chr19:53898486

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr19:53898486

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr19:53898486

 

GS18501 - var-GS18501-1100-36-ASM
hom A @ chr19:53898486

 

GS18502 - var-GS18502-1100-36-ASM
het A @ chr19:53898486

 

GS18504 - var-GS18504-1100-36-ASM
het A @ chr19:53898486

 

GS18505 - var-GS18505-1100-36-ASM
het A @ chr19:53898486

 

GS18508 - var-GS18508-1100-36-ASM
het A @ chr19:53898486

 

GS18517 - var-GS18517-1100-36-ASM
het A @ chr19:53898486

 

GS19017 - var-GS19017-1100-36-ASM
het A @ chr19:53898486

 

GS19020 - var-GS19020-1100-36-ASM
het A @ chr19:53898486

 

GS19025 - var-GS19025-1100-36-ASM
hom A @ chr19:53898486

 

GS19129 - var-GS19129-1100-36-ASM
het A @ chr19:53898486

 

GS19238 - var-GS19238-1100-36-ASM
het A @ chr19:53898486

 

GS19239 - var-GS19239-1100-36-ASM
hom A @ chr19:53898486

 

GS19240 - var-GS19240-1100-36-ASM
het A @ chr19:53898486

 

GS19649 - var-GS19649-1100-36-ASM
het A @ chr19:53898486

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr19:53898486

 

GS19670 - var-GS19670-1100-36-ASM
het A @ chr19:53898486

 

GS19701 - var-GS19701-1100-36-ASM
hom A @ chr19:53898486

 

GS19703 - var-GS19703-1100-36-ASM
het A @ chr19:53898486

 

GS19834 - var-GS19834-1100-36-ASM
hom A @ chr19:53898486

 

GS20502 - var-GS20502-1100-36-ASM
het A @ chr19:53898486

 

GS21767 - var-GS21767-1100-36-ASM
het A @ chr19:53898486

 

NA19240

 

Other external references
 

    dbSNP
  • rs601338
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [cyanocobalamin]
    Results from in vitro expression assays indicate that this polymorphism, which creates the translation termination codon, inactivates this allele. Approximately 20% of randomly-selected individuals were found to be homozygous for this enzyme-inactivating nonsense allele, in correspondence to the frequency of the non-secretor phenotype in most human populations.
    www.ncbi.nlm.nih.gov/pubmed/7876235

Other in silico analyses
 

  • NBLOSUM100 score = 10
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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