Yl Lau

Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease.

Inflammatory bowel disease is well recognized for a strong genetic involvement in its pathogenesis. Homozygous mutations in interleukin-10 receptor 1 (IL-10R1) identified by linkage analysis were shown to be involved in this disorder. However, the underlying molecular mechanism and the causal nature of the mutations in the disease process remain to be clarified. In this study, using whole exome sequencing, we identified novel compound heterozygous missense mutations in the extracellular domain of IL-10R1 in a Crohns disease patient from a non-consanguineous family. These mutations did not affect IL-10R1 expression, nor IL-10 binding. However, they abrogated IL-10R1 phosphorylation induced by IL-10, therefore leading to impaired STAT3 activation and suppression of inflammatory responses. After reconstitution with wild-type IL-10R1, the patient cells showed fully restored IL-10R function including IL-10-induced STAT3 activation and expression of suppressor of cytokine signaling 3. Thus, our results demonstrated that the mutations in IL-10R1 extracellular domain impair IL-10R1 activation rather than IL-10 binding, indicating these residues are important in IL-10 signal transduction through IL-10R1. The reconstitution data also confirmed the causality of the IL-10R1 mutations.

Identification of Bruton tyrosine kinase mutations in 12 Chinese patients with X-linked agammaglobulinaemia by long PCR-direct sequencing.

X‐linked agammaglobulinaemia (XLA) is an immunodeficiency caused by Bruton tyrosine kinase (BTK) gene mutations. The disease is characterized by recurrent bacterial infections and profound hypogammaglobulinemia with marked reduction or lack of mature B‐cells in the peripheral blood. Molecular characterization of BTK gene provides an opportunity for definitive diagnosis of XLA patients, especially for those with atypical phenotype resulting in a milder or late‐onset form of the disease. The diagnosis allows accurate carrier detection with subsequent genetic counselling and prenatal diagnosis. In this study, long polymerase chain reaction (PCR)‐direct sequencing analysis of the BTK gene in 12 unrelated Chinese XLA patients had been performed. Eight recurrent mutations and four novel mutations were identified. This is the first report of Chinese cases from three different East Asia regions together, including Hong Kong, Singapore and mainland China. Future clinical and genetic information from the undiagnosed Chinese XLA patients may provide insight into the genotype–phenotype correlations of BTK gene.

The genetics of macrocephaly, autistic spectrum disorders and developmental delay in Chinese children

M. Tamulaitiene, M. Jaramaviciene, J. Jaramavicius, V. Alekna. Faculty of Medicine of Vilnius University, Vilnius, Lithuania Objectives: To analyze the methods of treatment and outcome of hip fractures in Lithuania. Methods: This population-based retrospective study was performed collecting the data from all orthopaedic inpatient departments in Lithuania. The records of subjects, who were hospitalized because of primary hip fracture (ICD-10 codes S72.0, S72.1 and S72.2) at the age over 40 years in 2010, were examined. Methods of treatment were conservative and surgical, while the latter was divided into fixation by screws, plate or intramedullary nail (IN), and total hip arthroplasty (TA). The outcomes included death, transfer to another department, discharge home or long-term hospital, and rehabilitation. Results: In 2010, 2626 hip fractures occurred in Lithuania. The most common method used was osteosynthesis: fixation by plate accounted for 41.4%, screw – 21.1%), and by IN – in 3.4% of cases. TAwas used in 25.9% and conservative treatment – in 8.1% of patients. After fixation by screws, plates and IN, the majority of patients were discharged home (42.5%, 35.8% and 37.8%, respectively) or to long-term care hospital (24.5%, 22% and 32.2%, respectively). Otherwise, after TA, 70.1% of patients underwent rehabilitation. Among patients treated conservatively, 39.7% were transferred to another department, ant their mortality rate was highest (4.2%). Number of deaths was lowest after treatment with screws (0.7%). Conclusion: In 2010, in Lithuania, the majority of patients with hip fracture were treated with osteosynthesis using the external fixation. Rehabilitation was more often outcome of treatment using total hip arthroplasty, as compared to osteosynthesis.