RESUMO
The coexistence of abnormal keratinization and aberrant pigmentation in a number of cornification disorders has long suggested a mechanistic link between these two processes. Here, we deciphered the genetic basis of Cole disease, a rare autosomal-dominant genodermatosis featuring punctate keratoderma, patchy hypopigmentation, and uncommonly, cutaneous calcifications. Using a combination of exome and direct sequencing, we showed complete cosegregation of the disease phenotype with three heterozygous ENPP1 mutations in three unrelated families. All mutations were found to affect cysteine residues in the somatomedin-B-like 2 (SMB2) domain in the encoded protein, which has been implicated in insulin signaling. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which is responsible for the generation of inorganic pyrophosphate, a natural inhibitor of mineralization. Previously, biallelic mutations in ENPP1 were shown to underlie a number of recessive conditions characterized by ectopic calcification, thus providing evidence of profound phenotypic heterogeneity in ENPP1-associated genetic diseases.
Assuntos
Calcificação Fisiológica/genética , Hipopigmentação/genética , Ceratose/genética , Mutação , Diester Fosfórico Hidrolases/genética , Poroceratose/genética , Pirofosfatases/genética , Dermatopatias/genética , Exoma , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Transdução de Sinais/genética , Dermatopatias Genéticas/genética , Somatomedinas/genéticaRESUMO
Animal models of cerebral ischemia represent an important contribution to both our understanding of stroke mechanism and the development of new therapies. The technique of MCAO (middle cerebral artery occlusion) via ECA (external carotid artery) occlusion is widely utilized. Disruption of the ECA and its branches leads to impaired mastication and oral intake, post-surgical body weight loss, and poor neurological recovery which can possibly confound one's interpretation of rats' neurological outcome. Here, we developed a novel modified technique for MCAO without ligation or coagulation of the ECA and its branches using an approach via the internal carotid artery (ICA). In our modified technique, we perform an additional fixation of the filament in the ICA which improves the stability of the model and increases the homogeneity in stroke size. Compared with the original MCAO technique via the ECA, our modified technique via the ICA demonstrated decreased variability in the percent infarcted volume and brain edema, as well as a decreased mortality. Additionally, we observed that with our modified technique, rats gained more weight after surgery and there was less initial weight loss after the surgical preparation. Our new approach may serve as an effective model for stroke, and may lead to a better understanding of stoke pathophysiology and to the future development of new drugs and other neuroprotective agents.