A novel gastrokine, Gkn3, marks gastric atrophy and shows evidence of adaptive gene loss in humans.
OBJECTIVE
Gastrokines are stomach mucus cell-secreted proteins; 2 gastrokines are known, GKN1 and GKN2. Gastrokine expression is lost in gastric cancer, indicating a possible function in tumor suppression. We have identified a third gastrokine gene in mammals.


METHODS
Gkn3 was characterized by studies of molecular structure, evolutionary conservation, and tissue expression as well as transcriptional/translational outcome in mouse genetic models of gastric pathology. The functional consequences of Gkn3 overexpression were evaluated in transfected cell lines.


RESULTS
Gkn3 encodes a secreted (approximately 19 kilodalton) protein that is co-expressed with trefoil factor (Tff)2 in the distal stomach and discriminates a Griffinia simplicifolia lectin (GS)-II-positive mucus neck cell (MNC) subpopulation in the proximal stomach. In humans, widespread homozygosity for a premature stop codon polymorphism, W59X, has likely rendered GKN3 non-functional. Population genetic analysis revealed an ancestral GKN3 read-through allele that predominates in Africans and indicates the rapid expansion of W59X among non-Africans during recent evolution. Mouse Gkn3 expression is strongly up-regulated in (Tff2-deficient) gastric atrophy, a pre-cancerous state that is typically associated with Helicobacter pylori and marks a non-proliferative, GS-II positive lineage with features of spasmolytic polypeptide-expressing metaplasia (SPEM). Gkn3 overexpression inhibits proliferation in gastric epithelial cell lines, independently of incubation with recombinant human TFF2 or apoptosis.


CONCLUSIONS
Gkn3 encodes a novel, functionally distinct gastrokine that is overexpressed and might restrain epithelial cell proliferation in gastric atrophy. Spread of the human GKN3 stop allele W59X might have been selected for among non-Africans because of its effects on pre-neoplastic outcomes in the stomach.
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
Trevelyan R
TR
Menheniott
Anthony J
AJ
Peterson
Louise
L
O'Connor
Kai Syin
KS
Lee
Anastasia
A
Kalantzis
Ivanela
I
Kondova
Ronald E
RE
Bontrop
Katrina M
KM
Bell
Andrew S
AS
Giraud
D000222:Adaptation, Physiological / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D044466:Asian People / Q000235:genetics; D001284:Atrophy; D044383:Black People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D018389:Codon, Nonsense; D017124:Conserved Sequence; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D005787:Gene Frequency; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009077:Mucins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002679:Pan troglodytes; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D000071164:Trefoil Factor-2; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D018389:Codon, Nonsense; C549164:GKN3P protein, human; D008565:Membrane Proteins; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D011994:Recombinant Proteins; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; D000071164:Trefoil Factor-2; C549163:gastrokine 3 protein, mouse