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Differential regulation of two FLNA transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies.

  • Jenkins, Zandra A1
  • Macharg, Alison1
  • Chang, Cheng-Yee1
  • van Kogelenberg, Margriet1
  • Morgan, Tim1
  • Frentz, Sophia1
  • Wei, Wenhua1
  • Pilch, Jacek2
  • Hannibal, Mark3
  • Foulds, Nicola4
  • McGillivray, George5
  • Leventer, Richard J6
  • García-Miñaúr, Sixto7
  • Sugito, Stuart8
  • Nightingale, Scott9
  • Markie, David M10
  • Dudding, Tracy8
  • Kapur, Raj P11
  • Robertson, Stephen P1
  • 1 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. , (New Zealand)
  • 2 Department of Child Neurology, Medical University of Silesia, Katowice, Poland. , (Poland)
  • 3 Department of Medical Genetics, Seattle Children's Hospital, Seattle, Washington.
  • 4 Wessex Regional Genetics Service, Southampton, UK.
  • 5 Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne, Australia. , (Australia)
  • 6 Department of Neurology, Royal Children's Hospital, Murdoch Childrens Research Institute and University of Melbourne, Department of Paediatrics, Melbourne, Australia. , (Australia)
  • 7 Department of Medical Genetics, Hospital Universitario La Paz, Madrid, Spain. , (Spain)
  • 8 Hunter Genetics, Newcastle, Australia. , (Australia)
  • 9 University of Newcastle, GrowUpWell Priority Research Centre, Newcastle, UK.
  • 10 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. , (New Zealand)
  • 11 Department of Laboratories, Seattle Children's Hospital, Seattle, Washington.
Published Article
Human Mutation
Wiley (John Wiley & Sons)
Publication Date
Oct 12, 2017
DOI: 10.1002/humu.23355
PMID: 29024177


Loss-of-function mutations in the X-linked gene FLNA can lead to abnormal neuronal migration, vascular and cardiac defects, and congenital intestinal pseudo-obstruction (CIPO), the latter characterized by anomalous intestinal smooth muscle layering. Survival in male hemizygotes for such mutations is dependent on retention of residual FLNA function but it is unclear why a subgroup of males with mutations in the 5' end of the gene can present with CIPO alone. Here, we demonstrate evidence for the presence of two FLNA isoforms differing by 28 residues at the N-terminus initiated at ATG+1 and ATG+82 . A male with CIPO (c.18_19del) exclusively expressed FLNA ATG+82 , implicating the longer protein isoform (ATG+1 ) in smooth muscle development. In contrast, mutations leading to reduction of both isoforms are associated with compound phenotypes affecting the brain, heart, and intestine. RNA-seq data revealed three distinct transcription start sites, two of which produce a protein isoform utilizing ATG+1 while the third utilizes ATG+82 . Transcripts sponsoring translational initiation at ATG+1 predominate in intestinal smooth muscle, and are more abundant compared with the level measured in fibroblasts. Together these observations describe a new mechanism of tissue-specific regulation of FLNA that could reflect the differing mechanical requirements of these cell types during development.

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