Mouse FBN2 blocking peptide

Congenital contractural arachnodactyly (CCA, OMIM 121050), also known as Beals-Hecht syndrome, is an autosomal dominant disorder of connective tissue. CCA is characterized by arachnodactyly, dolichostenomelia, pectus deformities, kyphoscoliosis, congenital contractures and a crumpled appearance of the helix of the ear. The aim of this study is to identify the genetic cause of a 4-generation Chinese family of Tujia ethnicity with congenital contractural arachnodactyly by exome sequencing. The clinical features of patients in this family are consistent with CCA. A novel missense mutation, c.3769T>C (p.C1257R), in the fibrillin 2 gene (FBN2) was identified responsible for the genetic cause of our family with CCA. The p.C1257R mutation occurs in the 19th calcium-binding epidermal growth factor-like (cbEGF) domain. The amino acid residue cysteine in this domain is conserved among different species. Our findings suggest that exome sequencing is a powerful tool to discover mutation(s) in CCA. Our results may also provide new insights into the cause and diagnosis of CCA, and may have implications for genetic counseling and clinical management.

Objectives: The objective of the study was to identify novel medulloblastoma (MB) biomarkers through proteomic profiling, correlate it with the molecular subgroups of MB and assess the clinical significance. Methods: Archived paraffin embedded tumor tissue blocks from 118 MB patients, operated at our institute were retrieved. Clinical information was documented from the hospital database. Tumours were stratified into molecular subgroups using the IHC markers- beta Catenin, GAB-1, YAP-1 and p53. Six fresh MB tumour tissues and two control cerebellar tissues were subjected to proteomic profiling to study differential protein expression in molecular subgroups using high resolution mass spectrometry. Prominent signalling pathways activated in each subgroup were identified using the Panther pathway software. Results: Non WNT/SHH group was the most common (61.1 %), followed by SHH and WNT. p53 immunopositivity did not correlate with prognosis in any subgroup. Proteomic profiling revealed several novel proteins differentially expressed between MB molecular subgroups. Signalling pathways exclusively enriched in each molecular subgroup were also identified. The top upregulated proteins were PMEL and FBN2 in the WNT subgroup, SYNGR2 in the SHH subgroup and GFAP, IMPG2 and MAGEA10 in the Non WNT/Non SHH group. We validated GFAP by immunohistochemistry on the archived samples (n = 118) and noted two types of staining pattern in MBs - reactive (stellate) astrocytes and tumour cell staining. GFAP immunopositivity in tumor cells of SHH subgroup correlated with a better prognosis. Conclusions: Proteomic profile identified several novel proteins differentially regulated within the molecular subgroups that could serve as potential diagnostic /prognostic biomarkers. Notably, GFAP, which was derived from proteomics data, when validated by IHC, revealed a variable staining pattern in MB tumours. The prognostic significance of GFAP in SHH tumor patients further points at the heterogeneity of this subgroup. The study also throws light on the signaling pathways activated in MB and in turn its plausible role in the tumorigenesis.