title: SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease.
abstract: OBJECTIVE
  To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease.
  
  
  METHODS
  We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A>G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A>G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.
  
  
  RESULTS
  Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities <25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts.
  
  
  CONCLUSIONS
  We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy.
authors.affiliation: From the Département de Neurologie (A.E.-L.), Hôpitaux Universitaires, Strasbourg; INSERM U692 (A.E.-L.), Université de Strasbourg, France; Unit of Molecular Neurogenetics (D.G., L.M., M.Z.), Fondazione Istituto Neurologico Carlo Besta, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Service des Maladies Héréditaires du Métabolisme (M.C., M.M., S.P., B.M.deC.), Centre de Biotechnologie Cellulaire (I.R.), Unité de Cardiogénétique Moléculaire (D.B.), and Service de Neurobiologie (P.L.), Centre de Biologie et de Pathologie Est, CHU Lyon, Bron, France; and Département d'Anatomopathologie (B.L.), Hôpitaux Universitaires, Strasbourg, France.
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Maïté
authors.initials: M
authors.lastname: Chassagne
authors.forename: Martine
authors.initials: M
authors.lastname: Mayençon
authors.forename: Sylvie
authors.initials: S
authors.lastname: Padet
authors.forename: Laura
authors.initials: L
authors.lastname: Melchionda
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouvet
authors.forename: Béatrice
authors.initials: B
authors.lastname: Lannes
authors.forename: Dominique
authors.initials: D
authors.lastname: Bozon
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Mousson de Camaret
mesh_terms: D000328:Adult; D017668:Age of Onset; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C092928:Surf-1 protein
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