Nephronophthisis and retinal degeneration in tmem218-/- mice: a novel mouse model for Senior-Løken syndrome?

Mice deficient in TMEM218 (Tmem218(-/-) ) were generated as part of an effort to identify and validate pharmaceutically tractable targets for drug development through large-scale phenotypic screening of knockout mice. Routine diagnostics, expression analysis, histopathology, and electroretinogram analyses completed on Tmem218(-/-) mice identified a previously unknown role for TMEM218 in the development and function of the kidney and eye. The major observed phenotypes in Tmem218(-/-) mice were progressive cystic kidney disease and retinal degeneration. The renal lesions were characterized by diffuse renal cyst development with tubulointerstitial nephropathy and disruption of tubular basement membranes in essentially normal-sized kidneys. The retinal lesions were characterized by slow-onset loss of photoreceptors, which resulted in reduced electroretinogram responses. These renal and retinal lesions are most similar to those associated with nephronophthisis (NPHP) and retinitis pigmentosa in humans. At least 10% of NPHP cases present with extrarenal conditions, which most often include retinal degeneration. Senior-Løken syndrome is characterized by the concurrent development of autosomal recessive NPHP and retinitis pigmentosa. Since mutations in the known NPHP genes collectively account for only about 30% of NPHP cases, it is possible that TMEM218 could be involved in the development of similar ciliopathies in humans. In reviewing all other reported mouse models of NPHP, we suggest that Tmem218(-/-) mice could provide a useful model for elucidating the pathogenesis of cilia-associated disease in both the kidney and the retina, as well as in developing and testing novel therapeutic strategies for Senior-Løken syndrome.

Cardiomyopathy in α-kinase 3 (ALPK3)-deficient mice.

Cardiomyopathy developed in mice deficient for α-kinase 3 (ALPK3), a nuclear kinase previously implicated in the differentiation of cardiomyocytes. Alpk3 (-/-) mice were produced according to normal Mendelian ratios and appeared normal except for a nonprogressive cardiomyopathy that had features of both hypertrophic and dilated forms of cardiomyopathy. Cardiac hypertrophy in Alpk3 (-/-) mice was characterized by increased thickness of both left and right ventricular (LV and RV) walls and by markedly increased heart weight and increased heart weight/body weight and heart weight/tibia length ratios. Magnetic resonance imaging studies confirmed the increased thickness in both septal and LV free walls at end-diastole, although there was no significant change in LV wall thickness at end-systole. Myocardial hypertrophy was the predominant feature in Alpk3 (-/-) mice, but several changes more typically associated with dilated cardiomyopathy included a marked increase in end-diastolic and end-systolic LV volume, as well as reduced cardiac output, stroke volume, and ejection fractions, suggesting LV chamber dilation. Magnetic resonance imaging showed a 50% reduction in both septal and free wall LV contractility in Alpk3 (-/-) mice. Interstitial fibrosis and inflammation were notably absent in Alpk3 (-/-) mice; however, light and electron microscopy revealed altered cardiomyocyte architecture, characterized by reduced numbers of abnormal intercalated discs being associated with mild disarray of myofibrils. These lesions could account for the impaired contractility of the myofibrillar apparatus and contribute to the pathogenesis of cardiomyopathy in Alpk3 (-/-) mice.