@article {490,
	title = {Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.},
	journal = {Am J Hum Genet},
	volume = {102},
	year = {2018},
	month = {2018 05 03},
	pages = {858-873},
	abstract = {<p>The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in~vitro in affected individuals{\textquoteright} fibroblasts and skeletal muscle and in~vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.</p>},
	keywords = {Amino Acid Sequence, Animals, Atrophy, Base Sequence, Cerebellum, Child, Preschool, Exosome Multienzyme Ribonuclease Complex, Exosomes, Female, Fibroblasts, Gene Knockdown Techniques, Genetic Variation, Haplotypes, Humans, Infant, Male, Motor Neurons, Muscle, Skeletal, Pedigree, RNA-Binding Proteins, Spinal Cord, Zebrafish},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2018.03.011},
	author = {Burns, David T and Donkervoort, Sandra and M{\"u}ller, Juliane S and Knierim, Ellen and Bharucha-Goebel, Diana and Faqeih, Eissa Ali and Bell, Stephanie K and AlFaifi, Abdullah Y and Monies, Dorota and Millan, Francisca and Retterer, Kyle and Dyack, Sarah and MacKay, Sara and Morales-Gonzalez, Susanne and Giunta, Michele and Munro, Benjamin and Hudson, Gavin and Scavina, Mena and Baker, Laura and Massini, Tara C and Lek, Monkol and Hu, Ying and Ezzo, Daniel and Alkuraya, Fowzan S and Kang, Peter B and Griffin, Helen and Foley, A Reghan and Schuelke, Markus and Horvath, Rita and B{\"o}nnemann, Carsten G}
}
@article {294,
	title = {Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections.},
	journal = {Am J Hum Genet},
	volume = {93},
	year = {2013},
	month = {2013 Aug 08},
	pages = {398-404},
	abstract = {<p>Gene mutations that lead to decreased contraction of vascular smooth-muscle cells (SMCs) can cause inherited thoracic aortic aneurysms and dissections. Exome sequencing of distant relatives affected by thoracic aortic disease and subsequent Sanger sequencing of additional probands with familial thoracic aortic disease identified the same rare variant, PRKG1 c.530G>A (p.Arg177Gln), in four families. This mutation segregated with aortic disease in these families with a combined two-point LOD score of 7.88. The majority of affected individuals presented with acute aortic dissections (63\%) at relatively young ages (mean 31 years, range 17-51 years). PRKG1 encodes type I cGMP-dependent protein kinase (PKG-1), which is activated upon binding of cGMP and controls SMC relaxation. Although the p.Arg177Gln alteration disrupts binding to the high-affinity cGMP binding site within the regulatory domain, the altered PKG-1 is constitutively active even in the absence of cGMP. The increased PKG-1 activity leads to decreased phosphorylation of the myosin regulatory light chain in fibroblasts and is predicted to cause decreased contraction of vascular SMCs. Thus, identification of a gain-of-function mutation in PRKG1 as a cause of thoracic aortic disease provides further evidence that proper SMC contractile function is critical for maintaining the integrity of the thoracic aorta throughout a lifetime. </p>},
	keywords = {Acute Disease, Adolescent, Adult, Amino Acid Sequence, Aneurysm, Dissecting, Aorta, Thoracic, Aortic Aneurysm, Thoracic, Cyclic GMP, Cyclic GMP-Dependent Protein Kinase Type I, Exome, Female, Fibroblasts, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Molecular Sequence Data, Muscle Contraction, Muscle, Smooth, Vascular, Mutation, Myosin Light Chains, Pedigree},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2013.06.019},
	author = {Guo, Dong-Chuan and Regalado, Ellen and Casteel, Darren E and Santos-Cortez, Regie L and Gong, Limin and Kim, Jeong Joo and Dyack, Sarah and Horne, S Gabrielle and Chang, Guijuan and Jondeau, Guillaume and Boileau, Catherine and Coselli, Joseph S and Li, Zhenyu and Leal, Suzanne M and Shendure, Jay and Rieder, Mark J and Bamshad, Michael J and Nickerson, Deborah A and Kim, Choel and Milewicz, Dianna M}
}
