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Chen Z
; Migeon T
; Verpont MC
; Zaidan M
; Sado Y
; Kerjaschki D
; Ronco P
; Plaisier E
J Am Soc Nephrol
2016[Apr]; 27
(4
): 1042-54
PMID26260163
show ga
Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome
is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the
?1 chain of collagen IV, a major component of basement membranes. Patients
present with cerebral small vessel disease, retinal tortuosity, muscle cramps,
and kidney disease consisting of multiple renal cysts, chronic kidney failure,
and sometimes hematuria. Mutations producing HANAC syndrome localize within the
integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To
investigate the pathophysiology of HANAC syndrome, we generated mice harboring
the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1
G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation
without reduction of nephron number, causing albuminuria and hematuria in
newborns. The glomerular defects resolved within the first month, but glomerular
cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's
capsule was associated with metalloproteinase induction and activation of the
glomerular parietal epithelial cells that abnormally expressed CD44,?-SMA, ILK,
and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles.
Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and
urinary concentration defects. These results reveal a developmental role for the
?1?1?2 collagen IV molecule in the embryonic glomerular basement membrane,
affecting podocyte differentiation. The observed association between molecular
alteration of the collagenous network in Bowman's capsule of the mature kidney
and activation of parietal epithelial cells, matrix remodeling, and inflammation
may account for glomerular cyst development and CKD in patients with
COL4A1-related disorders.
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