Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts.

BACKGROUND: Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively. MATERIALS AND METHODS: Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families. RESULTS: Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%). CONCLUSION: Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.

Investigating the Protective Effects of a Citrus Flavonoid on the Retardation Morphogenesis of the Oligodendroglia-like Cell Line by Rnd2 Knockdown.

Recent discoveries suggest links between abnormalities in cell morphogenesis in the brain and the functional deficiency of molecules controlling signal transduction in glial cells such as oligodendroglia. Rnd2 is one such molecule and one of the Rho family monomeric GTP-binding proteins. Despite the currently known functions of Rnd2, its precise roles as it relates to cell morphogenesis and disease state remain to be elucidated. First, we showed that signaling through the loss of function of the rnd2 gene affected the regulation of oligodendroglial cell-like morphological differentiation using the FBD-102b cell line, which is often utilized as a differentiation model. The knockdown of Rnd2 using the clustered regularly interspaced palindromic repeats (CRISPR)/CasRx system or RNA interference was shown to slow morphological differentiation. Second, the knockdown of Prag1 or Fyn kinase, a signaling molecule acting downstream of Rnd2, slowed differentiation. Rnd2 or Prag1 knockdown also decreased Fyn phosphorylation, which is critical for its activation and for oligodendroglial cell differentiation and myelination. Of note, hesperetin, a citrus flavonoid with protective effects on oligodendroglial cells and neurons, can recover differentiation states induced by the knockdown of Rnd2/Prag1/Fyn. Here, we showed that signaling through Rnd2/Prag1/Fyn is involved in the regulation of oligodendroglial cell-like morphological differentiation. The effects of knocking down the signaling cascade molecule can be recovered by hesperetin, highlighting an important molecular structure involved in morphological differentiation.