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

Abstract

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the a1 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, a-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 a1a1a2 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.

HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect

“…21 In the present study, we provide new insights into the mechanisms of the skeletal muscle involvement, which is a major feature of this syndrome. Striated muscle BM contains from the a1a2(IV) collagen IV network.…”

“…Dex41/Dex41 mice that lack extracellular a1a1a2(IV) trimers, the Col4a1 p.G498V mutation did not completely abolish the assembly and secretion of the mutant protein in the muscle as well as in the kidney, 21 which may explain the less severe phenotype of HANAC Col4a1eG498V mutant mice. In vitro observations also showed that the degree of mutant a1(IV) intracellular retention was influenced by the location of the mutations, those located at the C-terminal part of the protein were associated with higher intracellular accumulation and more severe organ defects.…”

“…21 Mice were maintained in a specific pathogen-free environment and experiments were conducted in accordance with French government policies (Services Vétérinaires de la Santé et de la Production Animale, Ministère de l'Agriculture, agreement number B752001; Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche, agreement number 01108.03).…”

“…We previously showed the relevance of this murine strain for the analysis of HANAC renal defects. 21 In the present study, we describe the muscular phenotype of Col4a1 HANAC mutant animals.…”

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

“…In addition to the Col4a1;Col4a2 null mutation 14 , and a Col4a1 conditional mutation 101, 110 , there are presently 17 mutations reported in Col4a1 and Col4a2 that cause pathology in multiple tissues and organs 16, 17, 100, 104 (Fig. 1).…”