Genetic segregation of airway disease traits despite redundancy of calcium-activated chloride channel family members.
Complex airway diseases such as asthma and chronic obstructive pulmonary disease exhibit stereotyped traits (especially airway hyperreactivity and mucous cell metaplasia) that are variably expressed in each patient. Here, we used a mouse model for virus-induced long-term expression of these traits to determine whether individual traits can be genetically segregated and thereby linked to separate determinants. We showed that an F2 intercross population derived from susceptible and nonsusceptible mouse strains can manifest individual phenotypic extremes that exhibit one or the other disease trait. Functional genomic analysis of these extremes further indicated that a member of the calcium-activated chloride channel (CLCA) gene family designated mClca3 was inducible with mucous cell metaplasia but not airway hyperreactivity. In confirmation of this finding, we found that mClca3 gene transfer to mouse airway epithelium was sufficient to induce mucous cell metaplasia but not airway hyperreactivity. However, newly developed mClca3(-/-) mice exhibited the same degree of mucous cell metaplasia and airway hyperreactivity as wild-type mice. Bioinformatic analysis of the Clca locus led to the identification of mClca5, and gene transfer indicated that mClca5 also selectively drives mucous cell metaplasia. Thus, in addition to the capacity of CLCA family members to exhibit diverse functional activities, there is also preserved function so that more than one family member mediates mucous cell metaplasia. Nonetheless, Clca expression appears to be a selective determinant of mucous cell metaplasia so that shared homologies between CLCA family members may still represent a useful target for focused therapeutic intervention in hypersecretory airway disease.
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Anand C
AC
Patel
Jeffrey D
JD
Morton
Edy Y
EY
Kim
Yael
Y
Alevy
Suzanne
S
Swanson
Jennifer
J
Tucker
Guaming
G
Huang
Eugene
E
Agapov
Thomas E
TE
Phillips
Maria E
ME
Fuentes
Antonio
A
Iglesias
Dee
D
Aud
John D
JD
Allard
Karim
K
Dabbagh
Gary
G
Peltz
Michael J
MJ
Holtzman
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000378:metabolism; D001990:Bronchiolitis, Viral / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D003433:Crosses, Genetic; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D012140:Respiratory Tract Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D029082:Sendai virus
D018118:Chloride Channels; C492299:Clca2 protein, mouse; C116464:Clca3a1 protein, mouse; D009088:Mucoproteins; D012333:RNA, Messenger