Mice deficient in [alpha]-actinin-4 have severe glomerular disease

Kos, Claudine H.
Le, Tu Cam
Sinha, Sumita
Henderson, Joel M.
Kim, Sung Han
Sugimoto, Hikaru
Kalluri, Raghu
Gerszten, Robert E.
Pollak, Martin R.

¹ Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
² Cardiology Division and Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
³ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
⁴ Program in Matrix Biology, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Received for publication January 29, 2003, and accepted in revised form April 9, 2003.

Address correspondence to: Martin Pollak, HIM 534, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Phone: (617) 525-5840; Fax: (617) 525-5841; E-mail: [email protected].

Claudine H. Kos and Tu Cam Le contributed equally to this work.

Conflict of interest: The authors have declared that no conflict of interest exists.

Journal of Clinical Investigation 111(11):p 1683-1690, June 2003.

Dominantly inherited mutations inACTN4,which encodes [alpha]-actinin-4, cause a form of human focal and segmental glomerulosclerosis (FSGS). By homologous recombination in ES cells, we developed a mouse model deficient inActn4.Mice homozygous for the targeted allele have no detectable [alpha]-actinin-4 protein expression. The number of homozygous mice observed was lower than expected under mendelian inheritance. Surviving mice homozygous for the targeted allele show progressive proteinuria, glomerular disease, and typically death by several months of age. Light microscopic analysis shows extensive glomerular disease and proteinaceous casts. Electron microscopic examination shows focal areas of podocyte foot-process effacement in young mice, and diffuse effacement and globally disrupted podocyte morphology in older mice. Despite the widespread distribution of [alpha]-actinin-4, histologic examination of mice showed abnormalities only in the kidneys. In contrast to the dominantly inherited human form ofACTN4-associated FSGS, here we show that the absence of [alpha]-actinin-4 causes a recessive form of disease in mice. Cell motility, as measured by lymphocyte chemotaxis assays, was increased in the absence of [alpha]-actinin-4. We conclude that [alpha]-actinin-4 is required for normal glomerular function. We further conclude that the nonsarcomeric forms of [alpha]-actinin ([alpha]-actinin-1 and [alpha]-actinin-4) are not functionally redundant. In addition, these genetic studies demonstrate that the nonsarcomeric [alpha]-actinin-4 is involved in the regulation of cell movement.