title: Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis.
abstract: OBJECTIVE
  We describe a novel congenital motor neuron disease with early demise due to respiratory insufficiency with clinical overlap with spinal muscular atrophy with respiratory distress (SMARD) type 1 but lacking a mutation in the IGHMBP2 gene.
  
  
  METHODS
  Exome sequencing was used to identify a de novo mutation in the LAS1L gene in the proband. Pathogenicity of the mutation was validated using a zebrafish model by morpholino-mediated knockdown of las1l.
  
  
  RESULTS
  We identified a de novo mutation in the X-linked LAS1L gene in the proband (p.S477N). The mutation is in a highly conserved region of the LAS1L gene predicted to be deleterious by bioinformatic analysis. Morpholino-based knockdown of las1l, the orthologous gene in zebrafish, results in early lethality and disruption of muscle and peripheral nerve architecture. Coinjection of wild-type but not mutant human RNA results in partial rescue of the phenotype.
  
  
  CONCLUSIONS
  We report a patient with a SMARD phenotype due to a mutation in LAS1L, a gene important in coordinating processing of the 45S pre-rRNA and maturation of the large 60S ribosomal subunit. Similarly, the IGHMB2 gene associated with SMARD type 1 has been suggested to have an important role in ribosomal biogenesis from its role in processing the 45S pre-rRNA. We propose that disruption of ribosomal maturation may be a common pathogenic mechanism linking SMARD phenotypes caused by both IGHMBP2 and LAS1L.
authors.affiliation: From the Departments of Neurology (R.J.B., T.M.N., J.L.B., K.J.S.) and Pediatrics (R.J.B., T.J.S., L.X., J.L.B., K.J.S.), Pediatric Motor Disorders Research Program (R.J.B., T.M.N., B.N., K.J.S.), and Interdepartmental Program in Neurosciences (L.X.), University of Utah School of Medicine, Salt Lake City, UT; Ambry Genetics (W.Z., X.L., H-M.L., H.L., K.D.F.G., J-P.W., E.C.C., P.J.S.), Aliso Viejo, CA; Division of Genetics & Metabolism (E.C.C.), University of California, Irvine; and Department of Molecular Pathology (T.W.P.), Ohio State University, Columbus.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Butterfield
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Stevenson
authors.forename: Lingyan
authors.initials: L
authors.lastname: Xing
authors.forename: Tara M
authors.initials: TM
authors.lastname: Newcomb
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nelson
authors.forename: Wenqi
authors.initials: W
authors.lastname: Zeng
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Lu
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell Gonzalez
authors.forename: Jia-Perng
authors.initials: JP
authors.lastname: Wei
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Chao
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Prior
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Snyder
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Bonkowsky
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
mesh_terms: D000818:Animals; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009134:Muscular Atrophy, Spinal / Q000151:congenital / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D015027:Zebrafish
chemical_list: C552426:Las1L protein, human; D009687:Nuclear Proteins