Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens

Abstract

The eye lens is composed of fibre cells, which develop from the epithelial cells on the anterior surface of the lens. Differentiation into a lens fibre cell is accompanied by changes in cell shape, the expression of crystallins and the degradation of cellular organelles. The loss of organelles is believed to ensure the transparency of the lens, but the molecular mechanism behind this process is not known. Here we show that DLAD ('DNase II-like acid DNase', also called DNase IIbeta) is expressed in human and murine lens cells, and that mice deficient in the DLAD gene are incapable of degrading DNA during lens cell differentiation--the undigested DNA accumulates in the fibre cells. The DLAD-/- mice develop cataracts of the nucleus lentis, and their response to light on electroretinograms is severely reduced. These results indicate that DLAD is responsible for the degradation of nuclear DNA during lens cell differentiation, and that if DNA is left undigested in the lens, it causes cataracts of the nucleus lentis, blocking the light path.

Involvement of DNase II-Like Acid DNase in the Cataract Formation of the UPL Rat and the Shumiya Cataract Rat

“…7) DLAD has been found in mammals, and is reported to be expressed in the mouse lens, liver and human lens, salivary glands, and lungs. 8,9) In this study, we showed that DLAD mRNA was expressed in the lens, brain, lung, liver and pancreas in rats. In particular, stronger DLAD mRNA bands were found in the lens and liver (Fig.…”

“…These include genetic factors, diabetes, smoking, nutrition, the cumulative effect of X-rays, ultraviolet irradiation, and alteration in both endocrine and enzymatic equilibrium. [26][27][28][29][30][31] Recently, Nishimoto et al 9) reported that DLAD in the lens played an essential role in the degradation of nuclear DNA, and a lack of the DLAD gene causes nuclear cataracts. DLAD appears to be a divergent form of DNase II that catalyzes the hydrolysis of DNA into oligonucleotides under acidic conditions.…”

“…[4][5][6] DNase II-like acid DNase (also called DNase IIb; DLAD) 7,8) is an enzyme involved in differentiation into a lens fiber cell. Recently, Nishimoto et al 9) reported that a lack of the DLAD gene caused an inability to degrade DNA during lens cell differentiation, and the accumulates of undigested DNA in the fiber cells caused nuclear cataract in DLAD gene knockout mice. However, an appropriate model animal for investigating the change of DLAD with an increase in age has not yet been introduced.…”

Molecular chaperones as regulators of cell death

“…Apaf1 knockout mice have abnormal lens epithelium differentiation and inhibition of apoptosis in their lenses (Cecconi et al, 1998). DNase II-like acid DNase deficiency in mice produced congenital cataract formation with undigested DNA during lens differentiation (Nishimoto et al, 2003). Missense mutation of aA-crystallin (HspB4) and aB-crystallin was found in familiar congenital cataracts (Table 1).…”

DNA Degradation and Its Defects

“…Unlike DNase II, which is ubiquitously expressed in various tissues and cells, DLAD is specifically expressed in fiber cells of the optic lens (Fig. 3) (Nishimoto et al 2003). This avascular tissue, which focuses light onto the retina, consists of packed fiber cells bounded at the anterior by a monolayer of epithelial cells.…”