title: Neuropathy in a human without the PMP22 gene.
abstract: BACKGROUND
  Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations.
  
  
  OBJECTIVE
  To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene.
  
  
  METHODS
  The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice.
  
  
  METHODS
  Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee.
  
  
  METHODS
  A 7-year-old boy without the PMP22 gene.
  
  
  RESULTS
  Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers.
  
  
  CONCLUSIONS
  Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22.
authors.affiliation: Department of Neurology, Wayne State University, Detroit, Michigan, USA.
authors.forename: Mario Andre
authors.initials: MA
authors.lastname: Saporta
authors.forename: Istvan
authors.initials: I
authors.lastname: Katona
authors.forename: Xuebao
authors.initials: X
authors.lastname: Zhang
authors.forename: Helen P
authors.initials: HP
authors.lastname: Roper
authors.forename: Louise
authors.initials: L
authors.lastname: McClelland
authors.forename: Fiona
authors.initials: F
authors.lastname: Macdonald
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D002648:Child; D003711:Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human