Human molecular genetics
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Human molecular genetics · Dec 2015
Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death.
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1(+/-)) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1(+/-) carriers and alpha-synuclein-mediated neurotoxicity. ⋯ Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1(c.1276_1298del) zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders.
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Human molecular genetics · Jul 2015
Leucine-rich repeat kinase 2 deficiency is protective in rhabdomyolysis-induced kidney injury.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known genetic cause of Parkinson's disease, and LRRK2 is also linked to Crohn's and Hansen's disease. LRRK2 is expressed in many organs in mammals but is particularly abundant in the kidney. We find that LRRK2 protein is predominantly localized to collecting duct cells in the rat kidney, with much lower expression in other kidney cells. ⋯ Biochemical profiling of the LRRK2 KO kidneys using immunohistochemistry, proteomic and lipidomic analyses show a massive accumulation of hemoglobin and lipofuscin in renal tubules that account for the pigmentation. The proximal tubules demonstrate a corresponding up-regulation of the cytoprotective protein heme oxygenase-1 (HO-1) which is capable of mitigating acute kidney injury. The unusual kidney pathology of LRRK2 KO rats highlights several novel physiological roles for LRRK2 and provides indirect evidence for HO-1 expression as a protective mechanism in acute kidney injury in LRRK2 deficiency.
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Human molecular genetics · May 2015
Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.
Roughly one in three individuals is highly susceptible to motion sickness and yet the underlying causes of this condition are not well understood. Despite high heritability, no associated genetic factors have been discovered. Here, we conducted the first genome-wide association study on motion sickness in 80 494 individuals from the 23andMe database who were surveyed about car sickness. ⋯ We also show that two of these related phenotypes (PONV and migraines) share underlying genetic factors with motion sickness. These results point to the importance of the nervous system in motion sickness and suggest a role for glucose levels in motion-induced nausea and vomiting, a finding that may provide insight into other nausea-related phenotypes like PONV. They also highlight personal characteristics (e.g. being a poor sleeper) that correlate with motion sickness, findings that could help identify risk factors or treatments.
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Human molecular genetics · Apr 2015
Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice.
Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. ⋯ In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS.
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Human molecular genetics · Feb 2015
Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci.
Genetic risk loci have been identified for a wide range of diseases through genome-wide association studies (GWAS), but the relevant functional mechanisms have been identified for only a small proportion of these GWAS-identified loci. By integrating results from the largest current GWAS of chronic obstructive disease (COPD) with expression quantitative trait locus (eQTL) analysis in whole blood and sputum from 121 subjects with COPD from the ECLIPSE Study, this analysis identifies loci that are simultaneously associated with COPD and the expression of nearby genes (COPD eQTLs). ⋯ Transcription factor binding site (TFBS) analysis confirms that multiple COPD eQTL lead SNPs disrupt TFBS, and enhancer enrichment analysis for loci with the strongest colocalization signals showed enrichment for blood-related cell types (CD3 and CD4+ T cells, lymphoblastoid cell lines). In summary, integrative eQTL and GWAS analysis confirms that genetic control of gene expression plays a key role in the genetic architecture of COPD and identifies specific blood-related cell types as likely participants in the functional pathway from GWAS-associated variant to disease phenotype.