Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology.
The chromogranin/secretogranin proteins are costored and coreleased with catecholamines from secretory vesicles in chromaffin cells and noradrenergic neurons. Chromogranin A (CHGA) regulates catecholamine storage and release through intracellular (vesiculogenic) and extracellular (catecholamine release-inhibitory) mechanisms. CHGA is a candidate gene for autonomic dysfunction syndromes, including intermediate phenotypes that contribute to human hypertension. Here, we show a surprising pattern of CHGA variants that alter the expression and function of this gene, both in vivo and in vitro. Functional variants include both common alleles that quantitatively alter gene expression and rare alleles that qualitatively change the encoded product to alter the signaling potency of CHGA-derived catecholamine release-inhibitory catestatin peptides.
Wen
Gen
G
Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Mahata
Sushil K
SK
Cadman
Peter
P
Mahata
Manjula
M
Ghosh
Sajalendu
S
Mahapatra
Nitish R
NR
Rao
Fangwen
F
Stridsberg
Mats
M
Smith
Douglas W
DW
Mahboubi
Payam
P
Schork
Nicholas J
NJ
O'Connor
Daniel T
DT
Hamilton
Bruce A
BA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002395:Catecholamines / Q000502:physiology*; D053379:Chromogranin A; D002864:Chromogranins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010802:Phylogeny; D011110:Polymorphism, Genetic; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization
D002395:Catecholamines; D053379:Chromogranin A; D002864:Chromogranins