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The homology model of PMP22 suggests mutations resulting in peripheral neuropathy disrupt transmembrane helix packing.

ABSTRACT: Peripheral myelin protein 22 (PMP22) is a tetraspan membrane protein strongly expressed in myelinating Schwann cells of the peripheral nervous system. Myriad missense mutations in PMP22 result in varying degrees of peripheral neuropathy. We used Rosetta 3.5 to generate a homology model of PMP22 based on the recently published crystal structure of claudin-15. The model suggests that several mutations known to result in neuropathy act by disrupting transmembrane helix packing interactions. Our model also supports suggestions from previous studies that the first transmembrane helix is not tightly associated with the rest of the helical bundle.

SUBMITTER: Mittendorf KF

PROVIDER: S-EPMC4188248 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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The homology model of PMP22 suggests mutations resulting in peripheral neuropathy disrupt transmembrane helix packing.

Mittendorf Kathleen F KF Kroncke Brett M BM Meiler Jens J Sanders Charles R CR

Biochemistry 20140925 39

Peripheral myelin protein 22 (PMP22) is a tetraspan membrane protein strongly expressed in myelinating Schwann cells of the peripheral nervous system. Myriad missense mutations in PMP22 result in varying degrees of peripheral neuropathy. We used Rosetta 3.5 to generate a homology model of PMP22 based on the recently published crystal structure of claudin-15. The model suggests that several mutations known to result in neuropathy act by disrupting transmembrane helix packing interactions. Our mod ...[more]

PMID: 25243937

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Project description: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.

Dataset Information

The homology model of PMP22 suggests mutations resulting in peripheral neuropathy disrupt transmembrane helix packing.

Publications

The homology model of PMP22 suggests mutations resulting in peripheral neuropathy disrupt transmembrane helix packing.

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