title: Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel.
abstract: BACKGROUND
  CMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of "kinky" hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation.
  
  
  METHODS
  An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair.
  
  
  RESULTS
  Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement.
  
  
  CONCLUSIONS
  Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.
authors.affiliation: Department of Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Aharoni
authors.affiliation: Medical Research, RILD Wellcome Wolfson Centre (Level 4), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK.
authors.forename: Katy E S
authors.initials: KE
authors.lastname: Barwick
authors.affiliation: Department of Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.affiliation: Medical Research, RILD Wellcome Wolfson Centre (Level 4), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK.
authors.forename: Gaurav V
authors.initials: GV
authors.lastname: Harlalka
authors.affiliation: Department of Neurology, Schneider Children's Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Medical Research, RILD Wellcome Wolfson Centre (Level 4), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Chioza
authors.affiliation: Medical Genetics Unit, Floor 0, Jenner Wing, St. George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
authors.forename: Meriel M
authors.initials: MM
authors.lastname: McEntagart
authors.affiliation: The Pediatric Neurology and Developmental Unit, Loewenstein Rehabilitation Hospital, Raanana, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Mimouni-Bloch
authors.affiliation: Medical Research, Diabetes group, RILD Wellcome Wolfson Centre (Level 3), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Weedon
authors.affiliation: Medical Research, RILD Wellcome Wolfson Centre (Level 4), Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, EX2 5DW, UK. a.h.crosby@exeter.ac.uk.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003598:Cytoskeletal Proteins / Q000235:genetics*; D055724:Electrophysiological Phenomena; D005838:Genotype; D006801:Humans; D007557:Israel; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D014429:Twins, Dizygotic
chemical_list: D003598:Cytoskeletal Proteins; C416508:GAN protein, human
keywords: Charcot-Marie-Tooth disease type 2; GAN; Giant axonal neuropathy