Novel Compound Heterozygous Nonsense<i>PRX</i>Mutations in a Korean Dejerine-Sottas Neuropathy Family

Choi, Ye Ji; Hyun, Young Se; Nam, Soo Hyun; Koo, Heasoo; Hong, Young Bin; Chung, Ki Wha; Choi, Byung‐Ok

doi:10.3988/jcn.2015.11.1.92

Cited by 11 publications

(11 citation statements)

References 17 publications

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“…Charcot-Marie-Tooth (CMT) disease is a group of genetically heterogenous neuropathies that comprise the commonest disorders of the peripheral nervous system (PNS) 1 . CMT4F is a demyelinating autosomal recessive type caused by about 24 different mutations in the Periaxin ( PRX ) gene that manifests with motor and sensory disturbances 2 – 13 . Periaxin forms a complex with Dystrophin-Related Protein 2 (Drp2) and Dystroglycan (Dag) and this Prx/Drp2/Dag complex assembles adhesive appositions between the abaxonal surface of PNS myelin and the Schwann cell plasma membrane that are surrounded by cytoplasm-filled Cajal bands 14 , 15 .…”

Section: Introductionmentioning

confidence: 99%

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

Sherman¹,

Brophy²

2018

Wellcome Open Res

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Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin ( PRX) gene . Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F.

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Section: Introductionmentioning

confidence: 99%

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

Sherman¹,

Brophy²

2018

Wellcome Open Res

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“…Most PRX mutations causing human hereditary neuropathy introduce a premature stop codon into the sequence (74–76). In line with this, patients with such mutations have PRX expressed, but its size is smaller than in normal individuals (29,77).…”

Section: Discussionmentioning

confidence: 99%

Direct binding of the flexible C-terminal segment of periaxin to β4 integrin suggests a molecular basis for CMT4F

Raasakka

Linxweiler

Brophy

et al. 2019

Preprint

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The process of myelination in the nervous system requires coordinated formation of both transient and stable supramolecular complexes. Myelin-specific proteins play key roles in these assemblies, which may link membranes to each other or connect the myelinating cell cytoskeleton to the extracellular matrix. The myelin protein periaxin is known to play an important role in linking the Schwann cell cytoskeleton to the basal lamina through membrane receptors, such as the dystroglycan complex. Mutations that truncate periaxin from the C terminus cause demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 4F, indicating a function for the periaxin C-terminal region in myelination. We identified the cytoplasmic domain of β4 integrin as a specific high-affinity binding partner for periaxin. The C-terminal region of periaxin remains unfolded and flexible when bound to the third fibronectin type III domain of β4 integrin. Our data suggest that periaxin is able to link the Schwann cell cytoplasm to the basal lamina through a two-pronged interaction via different membrane protein complexes, which bind close to the N and C terminus of this elongated, flexible molecule.

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“…To date, dozens of patients have been described with around 30 different PRX mutations ( Figure 2 ). These include nonsense, missense, point, and frameshift mutations, 1 , 3 , 4 , 15 – 21 , 22 and most affect the synthesis of L-periaxin. Eleven pathogenic point mutations have been detected, 1 , 3 , 4 , 16 – 22 of which one is a missense mutation 15 , 18 while the remainder are nonsense mutations.…”

Section: Discussionmentioning

confidence: 99%

“…These include nonsense, missense, point, and frameshift mutations, 1 , 3 , 4 , 15 – 21 , 22 and most affect the synthesis of L-periaxin. Eleven pathogenic point mutations have been detected, 1 , 3 , 4 , 16 – 22 of which one is a missense mutation 15 , 18 while the remainder are nonsense mutations. Twenty-two patients were reported to harbor homozygous nonsense/missense mutations, 1 , 3 , 4 , 16 – 20 of whom 14 are from three families 1 , 3 , 4 , 17 and the remaining eight are sporadic.…”

Section: Discussionmentioning

confidence: 99%

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Novel mutation in the periaxin gene causal to Charcot–Marie–Tooth disease type 4F

et al. 2019

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Charcot–Marie–Tooth (CMT) disease is the most common hereditary neuropathy. Mutations in the periaxin gene ( PRX) can cause CMT type 4F, an autosomal recessive neuropathy, which is clinically characterized by slowly progressive distal muscle atrophy and weakness, with pes cavus deformity of the foot, and the absence of deep tendon reflexes. To date, dozens of reports of PRX mutations have been published worldwide, but none have been reported in Chinese patients. Here, we describe a 14-year-old Chinese boy with neuropathy characterized by slowly progressive limb weakness and atrophy, as well as sensory ataxia, whose cerebrospinal protein levels were 1627 mg/L. Genetic analysis identified a novel homozygous mutation, c.1174C>T (p.R392X), in exon 6 of PRX, which is the first case of its kind recorded in China.

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Novel Compound Heterozygous NonsensePRXMutations in a Korean Dejerine-Sottas Neuropathy Family

Cited by 11 publications

References 17 publications

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

Direct binding of the flexible C-terminal segment of periaxin to β4 integrin suggests a molecular basis for CMT4F

Novel mutation in the periaxin gene causal to Charcot–Marie–Tooth disease type 4F

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