A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited per ipheral motor and sensory neuropathies characterized by chronic distal weak ness with progressive muscular atrophy and sensory loss in the distal extre mities. Inheritance can be autosomal dominant, X-linked or autosomal recess ive (ARCMT), Recently, a locus responsible for a demyelinating form of ARCM T disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family. L- and S-periaxin are proteins of myelinating Schwann cell s and homozygous periaxin-null mice display extensive demyelination of myel inated fibers in the peripheral nervous system, which suggests that the per iaxin gene is a good candidate gene for an ARCMT disease. The human gene en coding the periaxins (PRX) was mapped to 19q13, in the CMT4F candidate inte rval. After characterizing the human PRX gene, we identified a nonsense R19 6X mutation in the Lebanese family which cosegregated with CMT, Histopathol ogical and immunohistochemical analysis of a sural nerve biopsy of one pati ent revealed common features with the mouse mutant and the absence of L-per iaxin from the myelin sheath. These data confirm the importance of the peri axin proteins to normal Schwann cell function and substantiate the utility of the periaxin-null mouse as a model of ARCMT disease.