Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor-encoding gene, RUNX2. To correlate different RUNX2 mutations with CCD clinical spectrum, we studied six independent Chinese CCD patients. In five patients, mutations were detected in the coding region of the RUNX2 gene, including two frameshift mutations and three missense mutations. Of these mutations, four were novel and one had previously been reported. All the detected mutations were exclusively clustered within the Runt domain that affected conserved residues in the Runt domain. In vitro green fluorescent protein fusion studies showed that the three mutations--R225L, 214fs and 172fs--interfered with nuclear accumulation of RUNX2 protein, while T200I mutation had no effect on the subcellular distribution of RUNX2. There was no marked phenotypic difference between patients in craniofacial and clavicles features, while the expressivity of supernumerary teeth in our patient cohort had a striking variation, even among family members. The occurrence of intrafamilial clinical variability raises the view that hypomorphic effects and genetic modifiers may alter the clinical expressivity of these mutations. Our results provide new genetic evidence that mutations involved in RUNX2 contribute to CCD.

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Microtubule-associated protein tau (MAPT) gene is compelling among the susceptibility genes of neurodegenerative diseases which include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Our meta-analysis aimed to find the association between MAPT and the risk of these diseases. Published literatures were retrieved from MEDLINE and other databases, and 82 case-control studies were recruited. Six haplotype tagging single-nucleotide polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9 and rs7521) and haplotypes (H2 and H1c) were significantly associated with the above diseases. The odds ratios (ORs) and 95 % confidence intervals (CIs) were evaluated by comparison in minor and major allele frequency using the R software. This study demonstrated that different variants in MAPT were associated with AD (rs2471738: OR= 1.04, 95%CI = 1.00 - 1.09; H2: OR = 0.94, 95% CI = 0.91 - 0.97), PD (H2: OR = 0.76, 95% CI = 0.74 - 0.79), PSP (rs242557: OR = 1. 96, 95% CI = 1. 71 - 2.25; rs2471738: OR = 1. 85, 95% CI = 1. 48 - 2.31; H2: OR = 0.20, 95% CI = 0.18 - 0.23), CBD (rs242557: OR = 2.51, 95%CI = 1. 66 -3.78; rs2471738: OR = 2.07, 95%CI = 1. 32 -3.23; H2: OR = OR = 0.30, 95% CI = 0.23 - 0.41) and ALS (H2: OR = 0.92, 95% CI = 0.86 - 0.98) instead of FTD (H2: OR = 1.02, 95% CI = 0.78 - 1.32). In conclusion, MAPT is associated with risk of neurodegenerative diseases, suggesting crucial roles of tau in neurodegenerative processes.

Background: The role of infectious agents in the development of Alzheimer's disease (AD) has long been debated, however, uncertainties still persist. Objective: We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. Methods: Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. Results: Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81-10.67; I 2 = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04-7.75; I 2 = 0%), Epstein-Barr virus (OR:1.45, 95% CI = 1.00-2.08; I 2 = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02-1.75; I 2 = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15-1.74; I 2 = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. Conclusion: These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future.