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Familial periventricular nodular heterotopia, epilepsy and Melnick–Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects
  1. Elena Parrini1,
  2. Davide Mei1,
  3. Maria Antonietta Pisanti2,
  4. Serena Catarzi3,
  5. Daniela Pucatti1,
  6. Claudia Bianchini1,
  7. Mario Mascalchi4,
  8. Enrico Bertini5,
  9. Amelia Morrone3,6,
  10. Maria Luigia Cavaliere2,
  11. Renzo Guerrini1
  1. 1Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital—University of Florence, Florence, Italy
  2. 2Medical Genetic Unit, AORN Cardarelli, Naples, Italy
  3. 3Molecular and Cell Biology Laboratory, Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Florence, Italy
  4. 4Quantitative and Functional Neuroradiology Research Program, Meyer Children Hospital and Careggi General Hospital, Florence, Italy
  5. 5Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Research Hospital, Rome, Italy
  6. 6Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Florence, Italy
  1. Correspondence to Professor Renzo Guerrini, Neurology and Neurogenetics Unit, Children's Hospital A. Meyer-University of Florence, Viale Pieraccini 24, Firenze 50139, Italy; renzo.guerrini{at}meyer.it

Abstract

Background Loss-of-function mutations of the FLNA gene cause a neuronal migration disorder defined as X-linked periventricular nodular heterotopia (PNH); gain-of-function mutations are associated with a group of X-linked skeletal dysplasias designed as otopalatodigital (OPD) spectrum. We describe a family in which a woman and her three daughters exhibited a complex phenotype combining PNH, epilepsy and Melnick–Needles syndrome (MNS), a skeletal disorder assigned to the OPD spectrum. All four individuals harboured a novel non-conservative missense mutation in FLNA exon 3.

Methods In all affected family members, we performed mutation analysis of the FLNA gene, RT-PCR, ultradeep sequencing analysis in FLNA cDNAs and western blot in lymphocyte cells to further characterise the mutation. We also assessed the effects on RT-PCR products of treatment of patients’ lymphocytes with cycloheximide, a nonsense mediated mRNA decay (NMD) inhibitor.

Results We identified a novel c.622G>C change in FLNA exon 3, leading to the substitution of a highly conserved aminoacid (p.Gly208Arg). Gel electrophoresis and ultradeep sequencing revealed the missense mutation as well as retention of intron 3. Cycloheximide treatment demonstrated that the aberrant mRNA transcript-retaining intron 3 is subjected to NMD. Western blot analysis confirmed reduced FLNA levels in lymphocyte cells.

Conclusions The novel c.622G>C substitution leads to two aberrant FLNA transcripts, one of which carries the missense mutation, plus a longer transcript resulting from intron 3 retention. We propose that the exceptional co-occurrence of PNH and MNS, two otherwise mutually exclusive allelic phenotypes, is the consequence of a single mutational event resulting in co-occurring gain-of-function and loss-of-function effects.

  • Periventricular nodular heterotopia
  • FLNA
  • epilepsy
  • Melnick-Needles syndrome
  • mutation

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