DHCR24 Gene Knockout Mice Demonstrate Lethal Dermopathy with Differentiation and Maturation Defects in the Epidermis

Abstract

Desmosterolosis is an autosomal recessive disorder due to mutations in the 3beta-hydroxysterol-Delta24 reductase (DHCR24) gene that encodes an enzyme catalyzing the conversion of desmosterol to cholesterol. To date, only two patients have been reported with severe developmental defects including craniofacial abnormalities and limb malformations. We employed mice with targeted disruption of DHCR24 to understand the pathophysiology of desmosterolosis. All DHCR24-/- mice died within a few hours after birth. Their skin was wrinkleless and less pliant, leading to restricted movement and inability to suck (empty stomach). DHCR24 gene was expressed abundantly in the epidermis of control but not of DHCR24-/- mice. Accordingly, cholesterol was not detected whereas desmosterol was abundant in the epidermis of DHCR24-/- mice. Skin histology revealed thickened epidermis with few and smaller keratohyaline granules. Aberrant expression of keratins such as keratins 6 and 14 suggested hyperproliferative hyperkeratosis with undifferentiated keratinocytes throughout the epidermis. Altered expression of filaggrin, loricrin, and involcrin were also observed in the epidermis of DHCR24-/-. These findings suggested impaired skin barrier function. Indeed, increased trans-epidermal water loss and permeability of Lucifer yellow were observed in DHCR24-/- mice. DHCR24 thus plays crucial role for skin development and its proper function.

Neuroprotective effects of the Alzheimer's disease-related gene seladin-1

“…These animals were around 25% smaller in size than DHCR24 C/C and DHCR24 C/K littermates at birth. In contrast to initial reports, it was subsequently demonstrated that these animals do not survive until adulthood: in fact, they show a lethal dermopathy at birth, associated with retention of epidermal water in agreement with similar observations in patients with desmosterolosis, and die within a few hours (Mirza et al 2006(Mirza et al , 2008.…”

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

“…Of note, mice with a deficiency of 3b-hydroxysterol-D24, the enzyme that catalyzes the conversion of desmosterol to cholesterol, have abundant desmosterol but no cholesterol in the epidermis. These animals die within a few hours after birth from an impaired cutaneous permeability, providing additional evidence for the importance of cholesterol for normal permeability barrier function (82). Together, these results demonstrate an important role for epidermal cholesterol synthesis in permeability barrier homeostasis.…”

The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

“…Similar phenotypic alterations, such as malformation of the nervous system, have also been observed in other mutant mice with a defect in cholesterol biosynthesis (Liu et al 1999, Tozawa et al 1999, Fitzky et al 2001. Interestingly, the mutant mice deficient in Ebp, Sc5d, Dhcr24 and Dhcr7 survive until birth (Derry et al 1999, Fitzky et al 2001, Krakowiak et al 2003, Wechsler et al 2003, Mirza et al 2006, while the HSD17B7KO and mice deficient in the steps prior to the HSD17B7 (Liu et al 1999, Tozawa et al 1999, Caldas et al 2005) present with embryonic lethal phenotypes.…”