title: Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies.
abstract: BACKGROUND
  Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a 1.4-megabase deletion at chromosome 17p11.2, which bears the PMP22 gene and other genes. However, whether other genes besides PMP22 contribute to the phenotype is unknown. Whether any mutation within the coding region of the PMP22 gene ultimately causes HNPP by reducing the amount of peripheral myelin protein 22 (PMP22) expressed in myelin is also unknown.
  
  
  OBJECTIVE
  To determine whether affected patients develop a phenotype identical to that found in HNPP and whether the leucine 7 frameshift (Leu7fs) mutation reduces PMP22 levels in myelin.
  
  
  METHODS
  We evaluated affected family members by neurological examination, electrophysiology, and skin biopsies. We identified a large family with a Leu7fs mutation of PMP22 (11 affected members across 3 generations) that predicts truncation of the protein prematurely and eliminates PMP22 expression from the mutant allele.
  
  
  RESULTS
  We found that PMP22 levels were reduced in peripheral nerve myelin in dermal skin biopsies in patients with an Leu7fs mutation. Through clinical and electrophysiological evaluation, we also found that patients with the Leu7fs mutation were indistinguishable from patients with HNPP caused by deletion. We also found that a length-dependent axonal loss became pronounced in elderly patients with Leu7fs mutations, similar to what has been described in heterozygous knockout mice (pmp22 +/-).
  
  
  CONCLUSIONS
  Taken together, these results confirm that the phenotypic expression is identical in patients with Leu7fs mutation and patients with HNPP caused by chromosome 17p11.2 deletion. They also demonstrate that reduction of PMP22 is sufficient to cause the full HNPP phenotype.
authors.affiliation: Department of Neurology, Wayne State University, 4201 St Antoine St, UHC-8D, Detroit, MI 48201, USA. junli@med.wayne.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Khaled
authors.initials: K
authors.lastname: Ghandour
authors.forename: Danijela
authors.initials: D
authors.lastname: Radovanovic
authors.forename: Danuijola
authors.initials: D
authors.lastname: Radovanovic
authors.forename: Rosemary R
authors.initials: RR
authors.lastname: Shy
authors.forename: Karen M
authors.initials: KM
authors.lastname: Krajewski
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D004568:Electrodiagnosis; D005260:Female; D016368:Frameshift Mutation; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D010525:Peripheral Nerves / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype
chemical_list: D005819:Genetic Markers; D009185:Myelin Proteins; C073687:PMP22 protein, human; D007930:Leucine