Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth.

Biallelic loss-of-function variants in TBC1D2B have been reported in five subjects with cognitive impairment and seizures with or without gingival overgrowth. TBC1D2B belongs to the family of Tre2-Bub2-Cdc16 (TBC)-domain containing RAB-specific GTPase activating proteins (TBC/RABGAPs). Here, we report five new subjects with biallelic TBC1D2B variants, including two siblings, and delineate the molecular and clinical features in the ten subjects known to date. One of the newly reported subjects was compound heterozygous for the TBC1D2B variants c.2584C>T; p.(Arg862Cys) and c.2758C>T; p.(Arg920*). In subject-derived fibroblasts, TBC1D2B mRNA level was similar to control cells, while the TBC1D2B protein amount was reduced by about half. In one of two siblings with a novel c.360+1G>T splice site variant, TBC1D2B transcript analysis revealed aberrantly spliced mRNAs and a drastically reduced TBC1D2B mRNA level in leukocytes. The molecular spectrum included 12 different TBC1D2B variants: seven nonsense, three frameshifts, one splice site, and one missense variant. Out of ten subjects, three had fibrous dysplasia of the mandible, two of which were diagnosed as cherubism. Most subjects developed gingival overgrowth. Half of the subjects had developmental delay. Seizures occurred in 80% of the subjects. Six subjects showed a progressive disease with mental deterioration. Brain imaging revealed cerebral and/or cerebellar atrophy with or without lateral ventricle dilatation. The TBC1D2B disorder is a progressive neurological disease with gingival overgrowth and abnormal mandible morphology. As TBC1D2B has been shown to positively regulate autophagy, defects in autophagy and the endolysosomal system could be associated with neuronal dysfunction and the neurodegenerative disease in the affected individuals.

Differentially regulated ADAMTS1, 8, 9, and 18 in pancreas adenocarcinoma.

INTRODUCTION: Despite recent diagnostic and therapeutic improvements, pancreas cancer remains one of the highly lethal cancers. The extracellular matrix (ECM) is a physiological barrier that limits the spread of cancer cells into surrounding tissues and distant organs. Disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a family of 19 proteases, which is involved in various biological processes such as ECM remodelling and anti-angiogenesis. AIM: To investigate the expression of ADAMTS1, 8, 9, and 18 proteinases in pancreas adenocarcinoma and its nodal metastasis. MATERIAL AND METHODS: The immunostaining status of ADAMTS1, 8, 9, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent pancreaticoduodenectomy for an adenocarcinoma located at the head of the pancreas. RESULTS: In semi-quantitive grading pathologically, ADAMTS1, 8, 9, and 18 were found to be highly stained in all cancerous pancreas samples compared with normal pancreas. In addition, the immune positivity of ADAMTS1, 9, and 18 was found to be higher in metastatic lymph nodes than in non-metastatic lymph tissue. Tumour size was correlated with ADAMTS9 and 18 expressions in cancerous pancreas. CONCLUSIONS: According to the data obtained from the study, we suggest that these four ADAMTSs may have significant roles in the tumorigenesis and nodal spread of pancreas adenocarcinoma.