2. Academic Validation
  3. Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies

Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies

  • Am J Hum Genet. 2018 Jul 5;103(1):115-124. doi: 10.1016/j.ajhg.2018.05.003.
Silvio Alessandro Di Gioia 1,  Sherin Shaaban 2,  Beyhan Tüysüz 3,  Nursel H Elcioglu 4,  Wai-Man Chan 5,  Caroline D Robson 6,  Kirsten Ecklund 6,  Nicole M Gilette 7,  Azmi Hamzaoglu 8,  Gulsen Akay Tayfun 9,  Elias I Traboulsi 10,  Elizabeth C Engle 11
Affiliations

Affiliations

  • 1 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA.
  • 2 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Istanbul University, Cerrahpasa Medical School, Department of Pediatric Genetics, Istanbul, Turkey.
  • 4 Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey; Eastern Mediterranean University Medical School, Cyprus, Mersin 10, Turkey.
  • 5 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • 6 Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
  • 8 Istanbul Spine Center at Florence Nightingale Hospital, Abide-i Hurriyet Cad. No:166, Sisli, 34381, Istanbul, Turkey.
  • 9 Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.
  • 10 Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 11 Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 29887215 DOI: 10.1016/j.ajhg.2018.05.003
Abstract

MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 bp frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.Gln8Leufs∗86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.

Keywords

MYF5; exome sequencing; extraocular muscle; genome sequencing; human genetics; myogenesis; ophthalmaplegia; rib anomalies; scoliosis; vertebral anomalies.

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