Hereditary angiopathy, nephropathy,
aneurysms, and
muscle cramps (
HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 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,α-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 α1α1α2
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.