A rare novel mutation in TECTA causes autosomal dominant nonsyndromic hearing loss in a Mongolian family

BACKGROUND: The genetic basis of autosomal dominant nonsyndromic hearing loss is complex. Genetic factors are responsible for approximately 50% of cases with congenital hearing loss. However, no previous studies have documented the clinical phenotype and genetic basis of autosomal dominant nonsyndromic hearing loss in Mongolians. METHODS: In this study, we performed exon capture sequencing of a Mongolian family with hereditary hearing loss and identified a novel mutation in TECTA gene, which encodes α -tectorin, a major component of the inner ear extracellular matrix that contacts the specialized sensory hair cells. RESULTS: The novel G → T missense mutation at nucleotide 6016 results in a substitution of amino acid aspartate at 2006 with tyrosine (Asp2006Tyr) in a highly conserved zona pellucida (ZP) domain of α-tectorin. The mutation is not found in control subjects from the same family with normal hearing and a genotype-phenotype correlation is observed. CONCLUSION: A novel missense mutation c.6016 G > T (p.Asp2006Tyr) of TECTA gene is a characteristic TECTA-related mutation which causes autosomal dominant nonsyndromic hearing loss. Our result indicated that mutation in TECTA gene is responsible for the hearing loss in this Mongolian family

Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease.

OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown. METHODS: We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model. RESULTS: ACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice. CONCLUSIONS: This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospect for a translational reassessment of ACHD presentation in the clinic

A novel DSPP mutation causes dentinogenesis imperfecta type II in a large Mongolian family

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that the clinical phenotypes of dentinogenesis imperfecta type II (DGI-II) may be caused by mutations in <it>dentin sialophosphoprotein </it>(<it>DSPP</it>). However, no previous studies have documented the clinical phenotype and genetic basis of DGI-II in a Mongolian family from China.</p> <p>Methods</p> <p>We identified a large five-generation Mongolian family from China with DGI-II, comprising 64 living family members of whom 22 were affected. Linkage analysis of five polymorphic markers flanking <it>DSPP </it>gene was used to genotype the families and to construct the haplotypes of these families. All five DSPP exons including the intron-exon boundaries were PCR-amplified and sequenced in 48 members of this large family.</p> <p>Results</p> <p>All affected individuals showed discoloration and severe attrition of their teeth, with obliterated pulp chambers and without progressive high frequency hearing loss or skeletal abnormalities. No recombination was found at five polymorphic markers flanking DSPP in the family. Direct DNA sequencing identified a novel A→G transition mutation adjacent to the donor splicing site within intron 3 in all affected individuals but not in the unaffected family members and 50 unrelated Mongolian individuals.</p> <p>Conclusion</p> <p>This study identified a novel mutation (IVS3+3A→G) in <it>DSPP</it>, which caused DGI-II in a large Mongolian family. This expands the spectrum of mutations leading to DGI-II.</p

Advances in the structural MRI study of major depressive disorder

DOI：10.3969/j.issn.1672-6731.2011.03.00

A magnetization transfer imaging study of young and middle ⁃age patients with major depressive disorder

Objective To explore the cerebral magnetization transfer ratio (MTR) changes in young and middle⁃age patients with major depressive disorder (MDD) and its correlation with the disease duration. Methods Thirty MDD patients and 30 healthy controls took part in the whole study. Patients were diagnosed by experienced psychiatrists according to Diagnostic and Statistical Manual of Mental Disorders Fouth Edition (DSM ⁃ Ⅳ) criteria (American Psychiatric Association, 1994). Severity of depression was assessed by 17⁃item Hamilton Depression Rating Scale (HAMD) and only patients who scored 18 or higher were included. Healthy controls were individually matched with the patients for age, sex, handedness and education. Magnetization transfer imaging (MTI) was acquired by using a 3.0T Siemens magnetic resonance imaging (MRI) system. MTR map calculation, normalization, smoothing and statistical analysis were all carried out in the software Statistical Parametric Mapping (SPM). A 2⁃sample t ⁃test was used for group comparison and a Pearson correlation was used to examine the relationship between MTR and disease duration in MDD patients. Results In SPM, we set the cluster level P 60 weeks); and MTR was higher in the left middle frontal gyrus, tempo ⁃ occipital boundary, bilateral anterior cingulate cortex and adjacent white matter in patients with shorter disease duration (≤ 60 weeks). Conclusion MDD presents cerebral MTR changes in different pattern along with disease progression, which may implicate the needs of longitudinal imaging study for MDD, and particularly the effect of long term antidepressant treatment exerting on brain structure and function should be emphasized. DOI：10.3969/j.issn.1672-6731.2011.03.00

Identification of Core Gene Biomarkers in Patients with Diabetic Cardiomyopathy

Diabetic cardiomyopathy (DCM) is a disorder of the myocardium in diabetic patients, which is one of the critical complications of diabetes giving rise to an increased mortality. However, the underlying mechanisms of DCM remain incompletely understood presently. This study was designed to screen the potential molecules and pathways implicated with DCM. GSE26887 involving 5 control individuals and 7 DCM patients was selected from the GEO database to identify the differentially expressed genes (DEGs). DAVID was applied to perform gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was also constructed to visualize the interactions among these DEGs. To further validate significant genes and pathways, quantitative real-time PCR (qPCR) and Western blot were performed. A total of 236 DEGs were captured, including 134 upregulated and 102 downregulated genes. GO, KEGG, and the PPI network disclosed that inflammation, immune disorders, metabolic disturbance, and mitochondrial dysfunction were significantly enriched in the development of DCM. Notably, IL6 was an upregulated hub gene with the highest connectivity degree, suggesting that it may interact with a great many molecules and pathways. Meanwhile, SOCS3 was also one of the top 15 hub genes in the PPI network. Herein, we detected the protein level of STAT3 and SOCS3 in a mouse model with DCM. Western blot results showed that the protein level of SOCS3 was significantly lower while phosphorylated-STAT3 (P-STAT3) was activated in mice with DCM. In vitro results also uncovered the similar alterations of SOCS3 and P-STAT3 in cardiomyocytes and cardiac fibroblasts induced by high glucose (HG). However, overexpression of SOCS3 could significantly reverse HG-induced cardiomyocyte hypertrophy and collagen synthesis of cardiac fibroblasts. Taken together, our analysis unveiled potential biomarkers and molecular mechanisms in DCM, which could be helpful to the diagnosis and treatment of DCM

Additional file 2 of Identification of a HOXD13 variant in a Mongolian family with incomplete penetrance syndactyly by exon sequencing

Supplementary Material

Additional file 3 of Identification of a HOXD13 variant in a Mongolian family with incomplete penetrance syndactyly by exon sequencing

Supplementary Material

A novel pathogenic variant in OSBPL2 linked to hereditary late-onset deafness in a Mongolian family

Abstract Background To investigate the clinical features and the underlying causal gene of a family with hereditary late-onset deafness in Inner Mongolia of China, and to provide evidence for the early genetic screening and diagnosis of this disease. Methods Family data were collected to draw a pedigree. Audiological testing and physical examination of the family members were conducted following questionnaire. Genomic DNA was extracted from peripheral blood of 5 family members (3 patients and 2 normal control) and subjected to whole genome sequencing for identifying deafness casual genes. The pathogenic variant in the deafness gene was further confirmed by Sanger sequencing. Results The family is composed of a total of 6 generations, with 53 traceable individuals. In this family,19 of them were diagnosed with post lingual deafness with the age of onset between 10 and 40 years, displaying delayed and progressive hearing loss. Patients with hearing loss showed bilateral symmetry and mild to severe sensorineural deafness. The pattern of deafness inheritance in this family is autosomal dominant. Whole genome sequencing identified a novel pathogenic frameshift mutation, c.158_159delAA (p.Gln53Arg fs*100) in the gene OSBPL2 (Oxysterol-binding protein-related protein 2, NM_144498.2), which is absent from genomic data of 201 unrelated normal subjects. This pathogenic variant was further validated by Sanger sequencing, and was found to co-segregate in this family. Conclusions Whole genome sequencing identified a two-nucleotide deletion in OSBPL2 (c.158_159delAA) as the pathogenic variant for deafness in the family. Our finding expands the mutational spectrum of OSBPL2 and contributes to the pathogenic variant list in genetic counseling for deafness screening