Peripheral myelin protein 22 is a protein that is produced by Schwann cells and is part of myelin (involved in enveloping nerves) in the peripheral nervous system.[1]. PMP22 gene is found on chromosome 17 at position 12.[1]. This protein has a vital role in maintaining myelin, protecting nerves from any physical pressure, and also involved in the growth of Schwann cells.[1]. Any physical pressure can result in disrupting the transmission of nerve impulse.[1]. Before PMP22 protein becomes a part of myelin, it is processed and packaged in structures called the endoplasmic reticulum and the golgi apparatus.[1]. The processing and packaging procedure is crucial for proper myelin function.[1]. A mutation that occurs with this protein can result of conditions such as Dejerine-Sottas syndrome and Charcot-Marie-Tooth disease Type IA (hereditary neuropathy).[2].
In Charcot-Marie-Tooth disease, there is a DNA duplication of chromosome 17p12 which results in neurological disorder.[1]. When there is an extra chromosome, there is excess PMP22 which does not allow the protein from being processed properly.[1]. Where there is unprocessed PMP22, it can affect Schwann cell activities and lead to demyelination (loss of myelin).[1]. The impairment of myelin formation decreases the capability of peripheral nerves to activate muscles or communicate information from sensory cells back to brain.[1]. When peripheral nerves fail to activate muscles or send information, it results in muscle atrophy of lower limbs and also reduces sensation.[1].
In hereditary neuropathy, there is a deletion of a copy of PMP22 gene from each cell and this decreases the amount of PMP22 protein.[1]. This disease can also be due to mutation of PMP22 gene, leading to a change in the size of the protein.[1]. When there is less PMP22 protein, the structure of myelin gets affected and thus also has an impact on the transmission of nerve impulse.[1]. Dejerine-Sottas syndrome can be caused by AD mutations of PO or PMP22 gene, or by AD mutations of EGR2 gene, or by AR mutations of some genes.[3].
Charcot-Marie-Tooth disease (type 1A) can occur anytime from childhood to late adulthood and the symptoms may include the following: muscle weakness in the feet, clumsiness, balance difficulties, absent or decreased reflexes, and foot abnormalities such as high arches (pes cavus), flat feet (pes planus), and curled toes (hammer toes).[4]. With this disease, an individual may also experience weakness in the hands leading to difficulty in everyday activities and may also experience a reduced sensitivity in touch, cold, and heat in the lower limbs. [4]. In few cases, hearing loss and loss of vision may occur. [4]. Dejerine-Sottas syndrome (hereditary neuropathy) can cause muscle weakness, atrophy, numbness, and decreased or absent tendon reflexes and such type of symptoms are caused by a mild compression of a nerve, particularly, the peroneal and ulnar nerves, and may also affect radial nerve, median nerve, and brachial plexus.[5]. High arches feet may be present but it is not as common as in CMT disease.[5]. When comparing both diseases, their symptoms are similar in that both cause muscle weakness/atrophy, pes cavus(high arches), and absent/reduced reflexes may be seen. In the past it has been shown that CMT 1A disease is due to demyelination but lately it has been discovered that CMT 1A is a disorder of dysmyelination which means that myelination is delayed and normal myelination is not achieved.[5]. In hereditary neuropathy, the disruption of myelin results in segmental demyelination and remyelination.[5].
There are many transcription factors that are vital in the regulation of myelination of Schwann cells, such as EGFR2, Sox10, and Oct6. [7]. The transcription factors and their up and downstream factors are involved in signaling network that regulates the expression of myelin protein, including PMP22. [7]. When PMP22 is overexpressed, the proliferation of Schwann cells is decreased but when there is a reduction in PMP22, then there is a raise in Schwann cells proliferation. [7]. PMP22 has a point mutation, known as TrJ, which suppresses Schwann cell proliferation. [7]. With EGR2 mutations, there may be hyp-dys/demyelinating neuropathy of various kinds such as Dejerine-Sottas syndrome and mild CMT1.[7]. In CMT 1A, when there is an extra chromosome, it causes suppression of transcription factors like Krox20 which is expressed in myelinating Schwann cells.[6]. A study showed that overexpressed PMP22 may increase the expression of purinoceptor (P2X7) which leads to entry of extracellular calcium into Schwann cells. [7]. Also, a decrease in cholesterol can affect myelination in which it would harm action potential propagation. [7]. CMT1A is associated with down-regulation of cholesterol synthetic pathway. [7].
From the NGLY-deficiency perspective, PMP22 is somewhat related to it neurologically. NGLY-deficiency displays peripheral neuropathy and weak muscle tone which is similar in PMP22 mutation diseases. NGLY1 deficiency is an autosomal recessive disease of the endoplasmic reticulum–associated degradation (ERAD) pathway which consists of a triad of symptoms such as neurological dysfunction, liver disease, and abnormal tear production. [8]. According to studies, NGLY1 has a vital role as a cytoplasmic component of ERAD pathway and along with AAA ATPase complex p97. [8]. The ERAD pathway is involved in recognizing and degrading misfolded glycoproteins. [8]. After the misfolded glycoproteins are recognized, they are translocated to the cytosol by the ERAD pathway in which they are then degraded by cytosoli enzymes including NGLY1.[8]. With the involvement of recognizing and degrading misfolded glycoproteins, NGLY1 can cause further breaking down of proteins and this leads to glycoproteins to enter the cylinder of 20S proteasome. [8]. Thus, NGLY1 deficiency would lead to accumulation of glycoproteins in the cytoplasm and this accumulation of unidentified matter explains the liver dysfunction in the disease. [8]. There are different mechanisms proposed for the neurological manifestations of NGLY1 deficiency. One mechanism suggests that impaired PNG1 function, an orthologue to NGLY1 causes improper innervations of organs through peripheral axons in C.elegans.[9]. Another mechanism suggest that a deficiency of NGLY1 leads to a decrease of myelinated nerve fibers and this could be due to the neurotoxic accumulation of misfolded proteins due to weakened ERAD function or secondary to inhibited myelin production by the ER.[9].
References:
1.https://ghr.nlm.nih.gov/gene/PMP22#location
2.https://www.ncbi.nlm.nih.gov/gene/5376
“PMP22 peripheral myelin protein 22 [ Homo sapiens (human) ]”
3.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570696/ “Dejerine–Sottas syndrome grown to maturity: overview of genetic and morphological heterogeneity and follow-up of 25 patients” , Anneke Gabreëls-Festen.
Abstract
Dejerine–Sottas syndrome (DSS) is an early onset demyelinating motor and sensory neuropathy with motor nerve conduction velocities below 12 m s−1. The phenotype is genetically heterogeneous, and autosomal dominant (AD) as well as autosomal recessive (AR) inheritance is described. Nerve pathology is highly variable. It is generally presumed that clinical course is severe, leading to wheelchair dependency at an early age. In this study we documented the clinical and pathological features in 25 patients with a DSS and we evaluated the clinical course. In our series 14 patients had an AD mutation and six were probably affected by an AR disorder. In three patients inheritance mode was unknown and two patients obviously suffered from an acquired disorder. The clinical course in all patients was documented. Nine of the 25 patients showed a moderate handicap in adult life; walking distance was still at least 1 km. Age at last investigation of the ambulant patients ranged from 22 to 62 years (mean 38.6 years), and ambulant patients were found in all genetic subgroups. We conclude that DSS, although in general denoting a more serious neuropathy than CMT1, does not imply a severe disability or wheelchair dependency in adult life.
4.https://ghr.nlm.nih.gov/condition/charcot-marie-tooth-disease#inheritance
5.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994927/
“PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies”, Barbara W van Paassen, 1 Anneke J van der Kooi,2 Karin Y van Spaendonck-Zwarts,1 Camiel Verhamme,2 Frank Baas,3 and Marianne de Visser2
Abstract: PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal.
6.https://academic.oup.com/brain/article/125/10/2213/300461 “PMP22 overexpression causes dysmyelination in mice” , A. Robaglia‐Schlupp J. Pizant J.‐C. Norreel E. Passage D. Sabéran‐DjoneidiJ.‐L. Ansaldi L. Vinay D. Figarella‐Branger N. Lévy F. Clarac P. Cau J.‐F. PellissierM. Fontés
Abstract: Charcot–Marie–Tooth (CMT) disease is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. A subform, CMT1A, is transmitted as an autosomal dominant trait. An estimated 75% of patients are affected. This disorder has been shown to be associated with the duplication of a 1.5 Mb region of the short arm of chromosome 17, in which the PMP22 gene has been mapped. We have constructed a murine model of CMT1A by inserting into the murine genome a human YAC containing peripheral myelin protein 22 (PMP22) and its flanking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron microscopy, morphometry, electrophysiology, nerve conduction and expression of specific markers (e.g. Krox20) in normal and pathological Schwann cells demonstrated that PMP22 overexpression leads to a defect in the myelination of axons. The largest axons are the most affected. Only a few demyelination/remyelination processes were observed. Moreover, PMP22 overexpression probably enhances collagen synthesis by fibroblasts, before myelination, demonstrating that structures other than Schwann cells are affected by PMP22 overexpression. Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease.
7.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594637/ “The PMP22 Gene and Its Related Diseases” ,
Jun Li,1,2,3,4 Brett Parker,1 Colin Martyn,1 Chandramohan Natarajan,1 and Jiasong Guo1
Abstract:
Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50% of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While over-expression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene.
8.https://www.nature.com/articles/gim201422 “Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum–associated degradation pathway” , Gregory M. Enns MB, ChB, Vandana Shashi MD, MBBS, Matthew Bainbridge PhD, Michael J. Gambello MD, PhD, Farah R. Zahir PhD, Thomas Bast MD, Rebecca Crimian MS, Kelly Schoch MS, Julia Platt MS, Rachel Cox MS, Jonathan A. Bernstein MD, PhD, Mena Scavina DO, Rhonda S. WalterMD, Audrey Bibb MS, Melanie Jones PhD, Madhuri Hegde PhD, Brett H. Graham MD, PhD, Anna C. Need PhD, Angelica Oviedo MD, Christian P. Schaaf MD, PhD, Sean Boyle PhD, Atul J. Butte MD, PhD, Rong Chen PhD, Michael J. Clark PhD, Rajini Haraksingh PhD, Tina M. Cowan PhD, Ping He MD, PhD, Sylvie Langlois MD, Huda Y. Zoghbi MD, Michael Snyder PhD, Richard A. Gibbs PhD, Hudson H. FreezePhD & David B. Goldstein PhD , FORGE Canada Consortium
Abstract:
Purpose:
The endoplasmic reticulum–associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum–associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.
Methods:
Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.
Results:
All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.
Conclusion:
NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum–associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.
9.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804755/ “NGLY1 Mutation Causes Neuromotor Impairment, Intellectual Disability, and Neuropathy”, Ahmet Okay Caglayan,1,#* Sinan Comu,2,# Jacob F. Baranoski,1 Yesim Parman,3 Hande Kaymakçalan,4Gozde Tugce Akgumus,1 Caner Caglar,1 Duygu Dolen,1 E. Zeynep Erson Omay,1 Akdes Serin Harmanci,1 Ketu Mishra,1 Hudson H. Freeze,5 Katsuhito Yasuno,1 Kaya Bilguvar,1 and Murat Gunel1,*
Abstract: N-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteosome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson’s disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA, p.Asn511LysfsX51). We hypothesize that this mutation causes the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function.