our understanding on genetic factors affecting nerve injury and regeneration is primarily derived from numerous mouse models .
alterations of nerve regeneration are then observed in these mice ( osterloh et al . , 2012 ; wilhelm et al . , 2012
) . although critical information has been learnt from these models , it is often difficult to know how these findings can be translated into humans
. the mechanical force during each injury can not be the same , which makes any controlled study formidable among humans with nerve injures .
are there any individuals or families with specific genetic mutations that would render neurological deficits when mechanical stress on these individuals is no more than ordinary physical activities ? these mechanical stresses result in no symptoms in normal subjects , but are sufficient to cause dysfunction of the nerves with the mutation .
hereditary neuropathy with liability to pressure palsies ( hnpp ) says  yes  to this question .
as its name denotes , this autosomal dominant inherited disorder typically presents with focal sensory loss and/or muscle weakness when the related peripheral nerves are challenged by mechanical stress .
for instance , a patient with hnpp sits with one leg crossed on the other leg , which imposes mechanical pressure on the peroneal nerve at the fibular head .
a half hour of this benign pressure is often sufficient to induce a foot drop on the crossed leg that may last hours to months in patients with hnpp ( earl et al . , 1964 ; li et al . ,
strenuous physical activities in hnpp patients , such as running 10 miles with a 50 lb backpack , may lead to severe arm paralysis and protracted recovery ( horowitz et al . , 2004 ) .
gene mapping has revealed that patients with hnpp are associated with a heterozygous deletion of chromosome 17p12 ( c17p12 ) ( chance et al . , 1993 ) .
humans with a heterozygous truncation mutation of pmp22 manifest an hnpp phenotype identical to that in patients with the heterozygous deletion of c17p12 , supporting a causal role of loss of pmp22 function but not other genes in c17p12 ( nicholson et al .
mice with heterozygous knockout of pmp22 gene recapitulate the pathology of humans with hnpp ( adlkofer et al . , 1995 ) .
application of mechanical compression on pmp22 mouse nerves induced conduction block ( failure of action potential propagation ) more rapidly than that in pmp22 mouse nerves .
this finding is well in line with the focal sensory loss and muscle weakness in hnpp patients when their nerves are exposed to mild mechanical stress ( li et al .
utilizing the pmp22 mouse model , molecular mechanism underlying the impaired action potential propagation in hnpp has been investigated lately ( guo et al . , 2014 ) .
it is primarily localized in adult myelinating schwann cells , while its expression is diffuse in the developing nervous system ( parmantier et al . , 1995 , 1997 ;
interestingly , demyelination is not found until the late stage of the disease ( bai et al . , 2010 ) .
although demyelination is widely regarded as one of the most important mechanisms which alter nerve conduction , effective nerve conduction is also thought to require a proper myelin seal through myelin junctions ( such as tight junctions , adherens junctions ) .
these junctions seal the spaces between adjacent myelin lamellae as well as spaces between the myelin and axolemma ( hartline and colman , 2007 ) .
we found that deficiency of pmp22 dislocates junction protein complexes in myelin ( figure 1 ) .
this change yields excessively permeable myelin that allows an entry of dextran molecules up to a size of 70 kda ( guo et al . , 2014 )
. myelin junction disruption ( modified from figure 6h  i in guo et al . , annals of neurology 2014 ) .
upper panel : myelin junctions in a pmp22 nerve fiber are depicted in paranodes and mesaxons .
schmidt - lanterman incisures in inter - nodes are omitted since junctions in the incisures have changes similar to those in paranodes and mesaxons .
lower panel : a pmp22 nerve fiber shows disruption or loss of junction protein complexes ( tight junctions , ad - herens junctions ) in paranodes and/or mesaxons . these junction pro - teins may be found in aberrant locations , including pernuclear regions of myelinating schwann cells .
abnormal assembly of these junctions ( including jam - c transmembrane adhesion ) also loosens adhesion between paranodal myelin lamellae ( arrow on the right ) .
these changes increase myelin permeability that shunts current out of nerve fiber in the absence of demyelination , called  functional demyelination  .
the severity of abnormally increased myelin permeability was found to vary in different nerve fibers ( guo et al . , 2014 ) , and would produce two different populations of myelinated nerve fibers .
those in the first group have severely  leaky  myelin that would shunt current out of nerve fibers , leading to failure of action potential propagation in the absence of demyelination .
those in the second group have a mildly increased permeability of myelin , which still allows action potential to propagate , but would compromise the safety factor of action potential propagation .
the nodes of ranvier in myelinated nerve fibers typically generate depolarizing currents five times higher than the minimum required for the induction of an action potential .
this surplus is called the safety factor ( kaji et al . , 2000 ) .
this partially compromised safety factor would put the pmp22-deficient nerve fiber at risk to conduction failure if the fiber is challenged by additional external factors , such as mechanical stress .
taken together , studies in hnpp reveal a new concept that specific human genetic factor , such as pmp22 , may critically affect human nerve susceptibility to injures and recovery after the trauma . one mechanism to achieve this biological effect is through pmp22 's regulation of myelin junction formation and stability .
there are three types of junctions in myelin , including tight junctions , adherens junctions , and septate junctions . the first two are often autotypic junctions between myelin laminae of the same cell .
the third one is situated between the most inner lamina of schwann cells and axolemma ( hartline and colman , 2007 ) .
desmosomes were initially reported in myelin , but were later proven to be adherens junction ( fannon et al . , 1995 ) . under freeze - fracture electron microscopy , tight junctions appear as micro - strands extruding out of the membrane ( tetzlaff , 1978 ) . in the peripheral nerve myelin , these junctions are localized in non - compact myelin such as paranodal loops , schmidt - lanterman incisures , and inner / outer mesaxons ( poliak et al . , 2002 ) .
the strands are formed by polymerization of claudins , a family of tetraspan membrane proteins .
c - terminals of claudins interact with a group of cytoplasmic proteins containing pdz - domains such as zo1 or zo2 ( itoh et al . , 1999 ) . on the other hand
, these pdz - containing proteins also interact with actins and link the tight junction strands to the cytoskeleton for junction stabilization ( hartsock and nelson , 2008 ) .
e - cadherins have a large glycosylated extracellular domain , a single transmembrane domain and a cytoplasmic tail at the c - terminal that interacts with catenins ( -catenin , -catenin and p120 catenin ) .
there is another family of proteins , called jam ( jam - a , jam - b and jam - c ) that expresses nearby junctions .
jam contains a large extracellular ig - domain , a transmembrane domain , and a cytoplasmic c - terminal .
interactions between the ig - domain of jam from two opposing membranes may form homotypic dimers .
2000a ) , sealing the opposing membranes juxtaposed to tight / adherens junctions , and further strengthening the seal of myelin inter - membrane space ( bazzoni et al . , 2000b ; ebnet et al . , 2000 ) .
ablation of jam - c in mice results in hnpp - like pathology and alters nerve conduction ( scheiermann et al . , 2007 ) . finally , septate junctions are localized between paranodal myelin loops and axolemma .
the protein constituents of septate junction include neurofascin-155 ( nf155 ) located at the tips of paranodal myelin loops and the nf155-interacting partners ( caspr and contactin ) on the axolemma . under freeze fracture
em , septate junctions ( also called transverse bands ) are ridges spiraling along the paranodal axolemma which bridge the tips of paranodal myelin loops and axolemma ( rosenbluth , 2009 ) .
removal of any septate junction protein detaches paranodal myelin loops from the axolemma and impairs action potential propagation ( bhat et al .
, 2001 ; boyle et al . , 2001 ; sherman et al . , 2005 )
our observation in pmp22 mice shows abnormal formation and maintenance of these tight / adherence junctions in pmp22 deficiency .
this finding not only offers a novel mechanism to explain nerve conduction defect in the disease ( guo et al . , 2014 ) , but also has additional physiological implications .
after the developmental stage , when the myelinated nerve fiber has matured , its diameter , internodal length and myelin thickness remain stable .
our study provides an alternative mechanism that may fine - tune conduction by tightening or loosening the myelin junctions .
acquired or sporadic diseases can be studied by utilizing genetic models . a typical example is those studies in amyotrophic lateral sclerosis ( als ) .
a variety of rodent genetic models , such as the sod1 and tdp43 transgenic mice , have been used to study the pathogenic mechanisms of the disease . while als patients with mutations in sod1 or tdp43 are rare , investigations using these transgenic mice have made remarkable contributions to our understanding in the pathogenesis of als in general ( swarup and julien , 2010 ) .
we believe that a similar advance in nerve injures could be achieved through the use of genetic models .
. this strategy should motivate investigators to seek more families that might reveal additional genetic factors relevant to nerve injures .
sh3tc2 ( src homology 3 domain and tetratricopeptide repeats ) may become the next candidate gene .
autosomal recessive mutations in sh3tc2 have been associated with an inherited peripheral nerve disease , called charcot - marie - tooth disease type-4c ( cmt4c ) .
patients with cmt4c usually present with an early onset neuropathy with severe axonal loss and dysmyelination ( kessali et al . , 1997 ) .
however , humans with heterozygous mutations in sh3tc2 may present with carpal tunnel syndrome only ( lupski et al . ,
it is tethered to cellular membrane via its myristic acid anchor and is involved in regulation of endosome recycling through its interaction with rab11 ( stendel et al . , 2010 ) .
how these molecular functions relate to nerve resistance to mechanical stress is still unknown . finally , nerve entrapments ( focal compression ) are common neurological conditions in humans ; including median nerve entrapment at the wrist ( carpal tunnel syndrome ) , ulnar nerve across the elbow , and peroneal nerve across the fibular head .
 genetic factors may be learnt from families with gene mutations that render nerve - injury susceptibility even to ordinary physical activities . 
 a typical example is hereditary neuropathy with liability to pressure palsies ( hnpp ) . 
 hnpp is caused by a heterozygous deletion of pmp22 gene . 
 pmp22 deficiency disrupts myelin junctions ( such as tight junction and adherens junctions ) , leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury . 
 this finding should motivate investigators to identify additional genetic factors contributing to nerve vulnerability of injury . 
Introduction
Nerves in humans with PMP22 deficiency exhibit susceptibility to mechanical pressure
Junction disruption and abnormally increased permeability in PMP22-deficient myelin
Lessons may be learnt from additional genetic mutations