2. Academic Validation
  3. MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance

MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance

  • Am J Hum Genet. 2018 Dec 6;103(6):1009-1021. doi: 10.1016/j.ajhg.2018.10.019.
William B Dobyns 1,  Kimberly A Aldinger 2,  Gisele E Ishak 3,  Ghayda M Mirzaa 4,  Andrew E Timms 5,  Megan E Grout 6,  Marjolein H G Dremmen 7,  Rachel Schot 8,  Laura Vandervore 8,  Marjon A van Slegtenhorst 8,  Martina Wilke 8,  Esmee Kasteleijn 8,  Arthur S Lee 9,  Brenda J Barry 10,  Katherine R Chao 11,  Krzysztof Szczałuba 12,  Joyce Kobori 13,  Andrea Hanson-Kahn 14,  Jonathan A Bernstein 15,  Lucinda Carr 16,  Felice D'Arco 16,  Kaori Miyana 17,  Tetsuya Okazaki 18,  Yoshiaki Saito 18,  Masayuki Sasaki 19,  Soma Das 20,  Marsha M Wheeler 21,  Michael J Bamshad 22,  Deborah A Nickerson 21,  University of Washington Center for Mendelian Genomics 23,  Center for Mendelian Genomics at the Broad Institute of MIT and Harvard 11,  Elizabeth C Engle 24,  Frans W Verheijen 8,  Dan Doherty 4,  Grazia M S Mancini 25
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Neurology, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. Electronic address: wbd@uw.edu.
  • 2 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 3 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Radiology, University of Washington, Seattle, WA 98195, USA.
  • 4 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 5 Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 6 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
  • 7 Department of Radiology, Erasmus MC University Medical Center, Rotterdam 3015 CN, the Netherlands; Division of Pediatric Radiology, Sophia Children's Hospital, Rotterdam 3015 CN, the Netherlands.
  • 8 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015 CN, the Netherlands.
  • 9 Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 10 Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
  • 11 Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 12 Department of Medical Genetics, Medical University of Warsaw, Warsaw 02-106, Poland.
  • 13 Department of Genetics, Permanente Medical Group, San Jose, CA 95123, USA.
  • 14 Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA.
  • 15 Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA.
  • 16 Department of Neuroradiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
  • 17 Department of Pediatrics, Japanese Red Cross Medical Center, Shibuya, Tokyo, Japan.
  • 18 Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.
  • 19 Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 20 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
  • 21 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA.
  • 22 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA.
  • 23 University of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA.
  • 24 Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department Ophthalmology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • 25 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam 3015 CN, the Netherlands. Electronic address: g.mancini@erasmusmc.nl.
PMID: 30471716 DOI: 10.1016/j.ajhg.2018.10.019
Abstract

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome Sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.

Keywords

ACF7; MACF1; actin; axonal pathfinding; brainstem hypoplasia; cilia; cytoskeleton; lissencephaly; microtubules; midline crossing.

Figures