title: A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis.
abstract: Hydranencephaly is a congenital anomaly leading to replacement of the cerebral hemispheres with a fluid-filled cyst. The goals of this work are to describe a novel autosomal-recessive syndrome that includes hydranencephaly (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH)); to identify its genetic cause(s) and to provide functional insight into pathomechanism.
  
  
  
  We used homozygosity mapping and exome sequencing to identify recessive mutations in a single family with three affected fetuses. Immunohistochemistry, RT-PCR and imaging in cell lines, and zebrafish models, were used to explore the function of the gene and the effect of the mutation.
  
  
  
  We identified a homozygous nonsense mutation inCEP55segregating with MARCH. Testing the effect of this allele on patient-derived cells indicated both a reduction of the overallCEP55message and the production of a message that likely gives rise to a truncated protein. Suppression or ablation ofcep55lin zebrafish embryos recapitulated key features of MARCH, most notably renal dysplasia, cerebellar hypoplasia and craniofacial abnormalities. These phenotypes could be rescued by full-length but not truncated humanCEP55message. Finally, we expressed the truncated form of CEP55 in human cells, where we observed a failure of truncated protein to localise to the midbody, leading to abscission failure and multinucleated daughter cells.
  
  
  
  CEP55loss of function mutations likely underlie MARCH, a novel multiple congenital anomaly syndrome. This association expands the involvement of centrosomal proteins in human genetic disorders by highlighting a role in midbody function.
authors.affiliation: Departments of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada.|Departments of Biochemistry and Medical Genetics, University of Manitoba, Manitoba, Canada.
authors.forename: Patrick
authors.identifier: 0000-0002-9673-795X
authors.initials: P
authors.lastname: Frosk
authors.affiliation: Departments of Biochemistry, University of Western Ontario, London, Ontario, Canada.|Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Philippe
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Carter S
authors.initials: CS
authors.lastname: Gunn
authors.affiliation: Departments of Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Brown
authors.affiliation: Departments of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada.|Departments of Biochemistry and Medical Genetics, University of Manitoba, Manitoba, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Chodirker
authors.affiliation: Departments of Biochemistry and Medical Genetics, University of Manitoba, Manitoba, Canada.
authors.forename: Louise
authors.initials: L
authors.lastname: Simard
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Russell
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Yangfan P
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Departments of Biochemistry, University of Western Ontario, London, Ontario, Canada.|Departments of Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Hegele
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Departments of Pathology, University of Manitoba, Manitoba, Canada.
authors.forename: Conrad
authors.initials: C
authors.lastname: Goerz
authors.affiliation: Departments of Pathology, University of Manitoba, Manitoba, Canada.|Diagnostic Services Manitoba, Manitoba, Canada.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Del Bigio
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D064113:CRISPR-Cas Systems / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D000072669:Gene Editing; D006801:Humans; D007223:Infant; D008297:Male; D008938:Mitosis / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D013347:Subcellular Fractions / Q000378:metabolism; D013577:Syndrome; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C505378:Cep55 protein, human; D009687:Nuclear Proteins; D029961:Zebrafish Proteins; C000599829:cep55l protein, zebrafish
keywords: Potter sequence; hydranencephaly; midbody; multinucleated neurons; renal dysplasia