A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy.
OBJECTIVE
To assess the possible correlations between the reported candidate genes (VEGFR3, FOXC2, ITGA9 and ITGB1) and the clinical response in fetuses with severe congenital chylothorax (CC) treated by prenatal OK-432 pleurodesis.


METHODS
We studied 12 unrelated fetuses with severe CC, receiving fetal therapy by OK-432 pleurodesis. Genotyping of the candidate genes and the clinical parameters of these 12 fetuses were investigated. Additional 96 control individuals were enrolled to evaluate the possible polymorphisms at these candidate genes in population.


RESULTS
A recurrent heterozygous missense mutation (c.1210G>A, p.G404S) was identified in the beta-propeller domain of integrin alpha(9) (ITGA9), a cell adhesion receptor, in four of the five fetuses who failed to respond to the OK-432 treatment. Computer modeling of the p.G404S substitution supported the deleterious nature of this mutation. Family analyses in three affected fetuses demonstrated that the heterozygous mutant allele is of parental origin, suggesting an autosomal recessive inheritance of this genetic defect.


CONCLUSIONS
To the best of our knowledge, this is the first insight into the possible link between ITGA9 and CC in human fetuses. The identification of pathogenetic mutations and their possible link to the clinical responses of particular treatments may contribute to better pregnancy counseling and management.
Ma
Gwo-Chin
GC
Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua, Taiwan.
Liu
Chin-San
CS
Chang
Shun-Ping
SP
Yeh
Kun-Tu
KT
Ke
Yu-Yuan
YY
Chen
Tze-Ho
TH
Wang
Boris Bao-Tyan
BB
Kuo
Shou-Jen
SJ
Shih
Jin-Chung
JC
Chen
Ming
M
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002916:Chylothorax / Q000188:drug therapy / Q000196:embryology* / Q000235:genetics*; D004285:Dogs; D005260:Female; D046128:Fetal Therapies / Q000379:methods; D051858:Forkhead Transcription Factors / Q000235:genetics; D005838:Genotype; D006801:Humans; D039001:Integrin alpha Chains / Q000737:chemistry / Q000235:genetics*; D016023:Integrins / Q000737:chemistry / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D002679:Pan troglodytes; D010844:Picibanil / Q000627:therapeutic use; D011247:Pregnancy; D011487:Protein Conformation; D051381:Rats; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051858:Forkhead Transcription Factors; C108257:ITGB1BP1 protein, human; D039001:Integrin alpha Chains; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C084613:integrin alpha9; C082078:mesenchyme fork head 1 protein; D010844:Picibanil; D040321:Vascular Endothelial Growth Factor Receptor-3