HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Society of Nephrology 2016-04, Vol.27 (4), p.1042-1054
Main Authors: Chen, Zhiyong, Migeon, Tiffany, Verpont, Marie-Christine, Zaidan, Mohamad, Sado, Yoshikazu, Kerjaschki, Dontscho, Ronco, Pierre, Plaisier, Emmanuelle
Format: Article
Language:English
Subjects:
Age Factors
Animals
Animals, Newborn
Basic Research
Collagen Type IV - genetics
Kidney Diseases, Cystic - etiology
Kidney Diseases, Cystic - metabolism
Kidney Glomerulus - metabolism
Mice
Muscle Cramp - complications
Muscle Cramp - genetics
Muscle Cramp - metabolism
Muscle Cramp - physiopathology
Mutation
Permeability
Raynaud Disease - complications
Raynaud Disease - genetics
Raynaud Disease - metabolism
Raynaud Disease - physiopathology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1046-6673
1533-3450
DOI:10.1681/ASN.2014121217