Search

Abstract The nervous and vascular systems, although functionally different, share many common regulators of function maintenance. Long non‐coding RNAs (lncRNAs) are important players in many biological processes and human disorders. We previously identified a role of MALAT1 in microvascular dysfunction. However, its role in neurodegeneration is still unknown. Here, we used the eye as the model to investigate the role of MALAT1 in retinal neurodegeneration. We show that MALAT1 expression is significantly up‐regulated in the retinas, Müller cells, and primary retinal ganglion cells (RGCs) upon stress. MALAT1 knockdown reduces reactive gliosis, Müller cell activation, and RGC survival in vivo and in vitro. MALAT1‐CREB binding maintains CREB phosphorylation by inhibiting PP2A‐mediated dephosphorylation, which leads to continuous CREB signaling activation. Clinical and animal experimentation suggests that MALAT1 dysfunction is implicated in neurodegenerative processes and several human disorders. Collectively, this study reveals that MALAT1 might regulate the development of retinal neurodegeneration through CREB signaling.

Febrile seizures (FS) are common in children, and the incidence is 2–5% before the age of 5 years. A four-generation Chinese family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis. Significant linkage was identified with markers on chromosome 3q26.2–26.33 with a maximum pairwise LOD score of >3.00. Fine mapping defined the new genetic locus within a 10.7-Mb region between markers D3S3656 and D3S1232. A maximum multipoint LOD score of 5.27 was detected at marker D3S1565. A previously reported CLCN2 gene for epilepsy was excluded as the disease-causing gene in the family by mutational analysis of all exons and exon–intron boundaries of CLCN2 and by haplotype analysis. Mutation analysis of KCNMB2 and KCNMB3, which were two potassium-channel genes in this linkage region, did not reveal a disease causing mutation. Our results identified another novel locus on chromosome 3q26.2–26.33, and future studies of the candidate genes at the locus will identify a new gene for combined FS and idiopathic epilepsies. [ABSTRACT FROM AUTHOR]

Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes ( SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3–p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897 ( θ = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP ( DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP. [ABSTRACT FROM AUTHOR]

Congenital nystagmus is characterized by involuntary, rhythmical, repeated oscillations of one or both eyes. We studied a large Chinese family with nystagmus as a prominent and consistent manifestation phenotype in nine patients to map and identify a disease-causing gene for nystagmus. X-linked recessive inheritance was observed in the family, and foveal hypoplasia was detected in some of the nine patients. The disease gene was mapped to an approximately 10.6 Mb region flanked by DXS996 and DXS7593 on Xp22 with a significant peak multipoint LOD score. Analysis of 21 candidate genes in the region revealed a novel p.S89F mutation in the second transmembrane domain of GPR143, a G protein-coupled receptor which causes ocular albinism when mutated. All male patients in the family were hemizygous for the mutation; the female carriers were heterozygous for the mutation. The p.S89F mutation was not identified in 100 normal females or 100 normal males. Our results indicate that a mutation in the GPR143 gene can cause a variant form of ocular albinism, with congenital nystagmus as the most prominent and only consistent finding in all patients in this Chinese family. These results expand the spectrum of clinical phenotypes associated with GPR143 mutations. [ABSTRACT FROM AUTHOR]