Neuropathy in a human without the PMP22 gene

Mario da Cunha Saporta, Istvan Katona, Xuebao Zhang, Helen P. Roper, Louise McClelland, Fiona Macdonald, Louise Brueton, Julian Blake, Ueli Suter, Mary M. Reilly, Michael E. Shy, Jun Li

Research output: Contribution to journalArticle

11 Citations (Scopus)

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. Design: The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. Setting: 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. Participant: 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.

Original languageEnglish (US)
Pages (from-to)814-821
Number of pages8
JournalArchives of Neurology
Volume68
Issue number6
DOIs
StatePublished - Jun 1 2011
Externally publishedYes

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Motor Neurons
Nerve Fibers
Genes
Haploinsufficiency
Schwann Cells
Peripheral Nervous System
Spinal Ganglia
Sensory Receptor Cells
Myelin Sheath
Tertiary Care Centers
Embryonic Development
Electron Microscopy
Extremities
Immunohistochemistry
Phenotype
Neurons
Muscles
Mutation
Gene
Neuron

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

da Cunha Saporta, M., Katona, I., Zhang, X., Roper, H. P., McClelland, L., Macdonald, F., ... Li, J. (2011). Neuropathy in a human without the PMP22 gene. Archives of Neurology, 68(6), 814-821. https://doi.org/10.1001/archneurol.2011.110

Neuropathy in a human without the PMP22 gene. / da Cunha Saporta, Mario; Katona, Istvan; Zhang, Xuebao; Roper, Helen P.; McClelland, Louise; Macdonald, Fiona; Brueton, Louise; Blake, Julian; Suter, Ueli; Reilly, Mary M.; Shy, Michael E.; Li, Jun.

In: Archives of Neurology, Vol. 68, No. 6, 01.06.2011, p. 814-821.

Research output: Contribution to journalArticle

da Cunha Saporta, M, Katona, I, Zhang, X, Roper, HP, McClelland, L, Macdonald, F, Brueton, L, Blake, J, Suter, U, Reilly, MM, Shy, ME & Li, J 2011, 'Neuropathy in a human without the PMP22 gene', Archives of Neurology, vol. 68, no. 6, pp. 814-821. https://doi.org/10.1001/archneurol.2011.110
da Cunha Saporta M, Katona I, Zhang X, Roper HP, McClelland L, Macdonald F et al. Neuropathy in a human without the PMP22 gene. Archives of Neurology. 2011 Jun 1;68(6):814-821. https://doi.org/10.1001/archneurol.2011.110
da Cunha Saporta, Mario ; Katona, Istvan ; Zhang, Xuebao ; Roper, Helen P. ; McClelland, Louise ; Macdonald, Fiona ; Brueton, Louise ; Blake, Julian ; Suter, Ueli ; Reilly, Mary M. ; Shy, Michael E. ; Li, Jun. / Neuropathy in a human without the PMP22 gene. In: Archives of Neurology. 2011 ; Vol. 68, No. 6. pp. 814-821.
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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. Design: The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. Setting: 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. Participant: 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.",
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AU - Brueton, Louise

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N2 - 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. Design: The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. Setting: 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. Participant: 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.

AB - 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. Design: The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. Setting: 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. Participant: 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.

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