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Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function. [ABSTRACT FROM AUTHOR]

Abstract: Recently three different FLNC mutations were related to a peculiar phenotype of dominant distal myopathy with a distinct involvement of the hand muscles. Objective: We report the detailed clinical findings and underlying genetic defect in the Bulgarian family. Methods: We performed neurological, electrophysiological, radiological and histopathological analyses of 13 patients and thirteen at-risk but asymptomatic individuals from three generations. Genome-wide parametric linkage analysis was followed by bidirectional sequencing of the filamin C (FLNC) gene. We characterized the identified nonsense mutation at cDNA and protein level. Results: Based on clinical findings, no known myopathy subtype was implicated in our distal myopathy patients. Light microscopic analysis of affected muscle tissue showed no specific hallmarks, however the electron microscopy revealed changes compatible with myofibrillar myopathy. Linkage studies delineated a 9.76Mb region on chromosome 7q22.1-q35 containing filamin C (FLNC), a gene previously associated with myofibrillar myopathy. Mutation analysis revealed a novel c.5160delC frameshift deletion in all patients. The mutation results in a premature stop codon (p.Phe1720LeufsX63) that triggers nonsense-mediated mRNA decay. FLNC transcript levels were reduced in muscle and lymphoblast cells from affected subjects and partial loss of FLNC in muscle tissue was confirmed by protein analysis. Conclusions: The FLNC mutation that we identified is distinct in terms of the associated phenotype, muscle morphology and underlying molecular mechanism, thus extending the currently recognized clinical and genetic spectrum of filaminopathies. We conclude that filamin C is a dosage-sensitive gene and that FLNC haploinsufficiency can cause a specific type of myopathy in humans. [Copyright &y& Elsevier]

Spinal muscular atrophy (SMA) refers to a group of genetic disorders characterized by degeneration of anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by deleterious SMN1 mutations in 5q13. Nowadays a growing number of conditions are designated as non-5q forms of SMA. Materials and methods: A four-generation Bulgarian family with 11 affected members and one sporadic patient afflicted with autosomal dominant proximal SMA underwent detailed neurological examination and testing of muscle strength. Evaluation of serum creatine phosphokinase (CPK) levels and electromyography (EMG) were performed in 6 subjects. The molecular-genetic analysis encompassed genome-wide linkage analysis and whole-exome sequencing. The clinical onset was in childhood, varying between 1 and 6 years (mean 3.17 ± 1.70 years). The affected presented with delayed motor milestones, such as walking, difficulties in getting upright from a squatting position and in climbing stairs, a waddling gait, and slow running. The weakness was limited to the lower limbs and did not show significant progression over time, given that the oldest affected individuals still remained ambulatory into the fifth decade. Symmetric wasting was most prominent in the hip muscles, whereas distal leg muscles seemed atrophic in the older family members. EMG analysis proved anterior horn involvement. Serum creatine phosphokinase (CPK) levels were mostly normal. The genome-wide linkage analysis and whole-exome sequencing found a heterozygous de novo c.320C>T (p. Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2) in the 11 affected from the four-generation family and c.2321A>G (p. Glu774Gly) in the sporadic case. Our study identifies BICD2 gene mutations as a cause of the increasing number non-5q linked SMA and highlights its importance in the motor neuron function in humans. [ABSTRACT FROM AUTHOR]