title: MFN2 deletion of exons 7 and 8: founder mutation in the UK population.
abstract: Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot-Marie-Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi-dominant kindreds have also been described. We previously reported a deletion of exons 7 and 8 resulting in nonsense-mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives were collected. MFN2 Sanger sequencing, multiplex ligation probe amplification, and haplotype analysis were performed. A severe early-onset CMT phenotype was seen in all cases: progressive distal weakness, wasting, and sensory loss from infancy or early childhood. Optic atrophy (four of five) and wheelchair dependency in childhood were common (four of five). All were compound heterozygous for a deletion of exons 7 and 8 in MFN2 with another previously reported pathogenic mutation (Phe216Ser, Thr362Met, and Arg707Trp). Carrier parents and relatives were unaffected (age range: 24-82 years). Haplotype analysis confirmed that the deletion had a common founder in all families.
authors.affiliation: MRC Centre for Neuromuscular diseases, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Aisling S
authors.initials: AS
authors.lastname: Carr
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Jacob
authors.initials: J
authors.lastname: Wilson
authors.affiliation: MRC Centre for Neuromuscular diseases, National Hospital for Neurology and Neurosurgery, London, UK.|Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", UC and CIBERNED, Santander, Spain.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Pelayo-Negro
authors.affiliation: MRC Centre for Neuromuscular diseases, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Laura
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Nanji
authors.affiliation: Department of Neurology, The Walton Centre, Liverpool, UK.
authors.forename: James
authors.initials: J
authors.lastname: Holt
authors.affiliation: Department of Neurology, Charing Cross Hospital, London, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vaughan
authors.affiliation: Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: MRC Centre for Neuromuscular diseases, National Hospital for Neurology and Neurosurgery, London, UK.|Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.affiliation: MRC Centre for Neuromuscular diseases, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology*; D002872:Chromosome Deletion; D004739:England; D005091:Exons; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D010375:Pedigree; D014852:Wales; D055815:Young Adult
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: Charcot-Marie-Tooth disease; inherited neuropathy; mitofusin 2