A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene.
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Charcot-Marie-Tooth (CMT) disease is the most common inherited motor and sensory neuropathy. The axonal form of the disease is designated as "CMT type 2" (CMT2). Although four loci known to be implicated in autosomal dominant CMT2 have been mapped thus far (on 1p35-p36, 3q13. 1, 3q13-q22, and 7p14), no one causative gene is yet known. A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genomewide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 5' region of the neurofilament-light gene (NF-L). Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders. Screening of affected family members for mutations in the NF-L gene and in the tightly linked neurofilament-medium gene (NF-M) revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a conserved Gln333 amino acid to proline. This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype. (+info)
Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene.
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Autosomal recessive Charcot-Marie-Tooth disease (CMT) type 4 (CMT4) is a complex group of demyelinating hereditary motor and sensory neuropathies presenting genetic heterogeneity. Five different subtypes that correspond to six different chromosomal locations have been described. We hereby report a large inbred Lebanese family affected with autosomal recessive CMT4, in whom we have excluded linkage to the already-known loci. The results of a genomewide search demonstrated linkage to a locus on chromosome 19q13.1-13.3, over an 8.5-cM interval between markers D19S220 and D19S412. A maximum pairwise LOD score of 5.37 for marker D19S420, at recombination fraction [theta].00, and a multipoint LOD score of 10.3 for marker D19S881, at straight theta = .00, strongly supported linkage to this locus. Clinical features and the results of histopathologic studies confirm that the disease affecting this family constitutes a previously unknown demyelinating autosomal recessive CMT subtype known as "CMT4F." The myelin-associated glycoprotein (MAG) gene, located on 19q13.1 and specifically expressed in the CNS and the peripheral nervous system, was ruled out as being the gene responsible for this form of CMT. (+info)
Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins.
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More than 130 different mutations in the gap junction integral plasma membrane protein connexin32 (Cx32) have been linked to the human peripheral neuropathy X-linked Charcot-Marie-Tooth disease (CMTX). How these various mutants are processed by the cell and the mechanism(s) by which they cause CMTX are unknown. To address these issues, we have studied the intracellular transport, assembly, and degradation of three CMTX-linked Cx32 mutants stably expressed in PC12 cells. Each mutant had a distinct fate: E208K Cx32 appeared to be retained in the endoplasmic reticulum (ER), whereas both the E186K and R142W mutants were transported to perinuclear compartments from which they trafficked either to lysosomes (R142W Cx32) or back to the ER (E186K Cx32). Despite these differences, each mutant was soluble in nonionic detergent but unable to assemble into homomeric connexons. Degradation of both mutant and wild-type connexins was rapid (t(1/2) < 3 h) and took place at least in part in the ER by a process sensitive to proteasome inhibitors. The mutants studied are therefore unlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared from the cell by quality control processes that prevent abnormal connexin molecules from traversing the secretory pathway. (+info)
Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A.
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Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration. (+info)
Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.
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We report on a large four-generation Austrian family with autosomal dominant distal hereditary motor neuronopathy type V (distal HMN V). Forty-seven at-risk family members, of whom 21 were definitely affected, underwent detailed clinical, electrophysiological and genetic studies. The age at onset was in the second decade of life in most affected individuals, but clinical presentation was rather variable. While the majority of patients were primarily disabled by progressive asymmetrical wasting of the thenar and the first dorsal interosseus muscles, others had marked foot deformity and gait disturbance with the occasional absence of hand involvement. Sensation sense was normal except for the reduced response to vibration. Many individuals showed brisk tendon reflexes and some elevated muscle tone in the lower limbs, but extensor plantar responses were rarely observed. Electrophysiological evaluation revealed normal or reduced motor nerve conduction velocities, normal or prolonged distal motor latencies, and low compound motor action potentials, depending on the degree of muscle wasting. Sensory nerve studies were usually within the normal range or slightly to moderately abnormal in older or severely affected persons. Electromyography showed high-amplitude motor unit potentials and reduced recruitment compatible with anterior horn cell degeneration. Central motor conduction times were prolonged in two-thirds of the patients. Molecular genetic studies excluded Charcot-Marie-Tooth 1A syndrome and proximal spinal muscular atrophy linked to chromosome 5q as well as the known gene loci for distal HMN II on chromosome 12q, HMN V on chromosome 7p and juvenile amyotrophic lateral sclerosis on chromosome 9q. The findings in this family thus provide detailed clinical and electrophysiological information on HMN V and demonstrate broad phenotypic variability in this disorder. Hallmark features are discussed that appear to be most reliable to differentiate this type of HMN V from other variants of hereditary neuropathies, and a set of diagnostic criteria is proposed. Furthermore, this is the first report of prolonged central motor conduction times in HMN V, which indicates additional involvement of the central motor pathways in this disease. Finally, molecular genetic studies demonstrate genetic heterogeneity, suggesting the existence of at least a second genetic subtype in HMN V. (+info)
A novel locus for autosomal recessive peripheral neuropathy in the EGR2 region on 10q23.
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During our studies of Romany (Gypsy) families with hereditary motor and sensory neuropathy-Lom, we have identified a large kindred with two independently segregating autosomal recessive neuropathies. The novel disorder, named "hereditary motor and sensory neuropathy-Russe" (HMSNR), presented as a severe disabling form of Charcot-Marie-Tooth disease with prominent sensory loss, moderately reduced motor nerve conduction velocity, and a high threshold for electrical nerve stimulation. A genome scan in two branches of the large kindred detected linkage to the 10q22-q23 region containing the early growth response 2 gene (EGR2), a transcription factor with a key role in peripheral nerve myelination. The results of sequence analysis and the detection of an intragenic polymorphism allowed us to exclude EGR2 as the HMSNR gene. Further analysis done using linkage and recombination mapping refined the position of the HMSNR gene to a small interval on 10q23.2, flanked by markers D10S581 and D10S1742, telomeric to EGR2. In this interval, a conserved seven-marker haplotype is shared by all disease chromosomes, suggesting a single founder mutation. The homozygosity region is contained in bacterial-artificial-chromosome contig 1570 of the Sanger Centre physical map and has an estimated physical size of approximately 500 kb. (+info)
Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate.
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An increasing number of human diseases and syndromes are being found to result from micro-duplications or microdeletions arising from meiotic recombination between homologous repeats on the same chromosome. The first microduplication syndrome delineated, Charcot-Marie-Tooth disease type 1A (CMT1A), results from unequal crossing over between two >98% identical 24 kb repeats (CMT1A-REPs) on chromosome 17. In addition to its medical significance, the CMT1A region has features that make it a unique resource for detailed analysis of human unequal recombination. Previous studies of CMT1A patients showed that the majority of unequal crossovers occurred within a small region (<1 kb) of the REPs suggesting the presence of a recombination hot-spot. We directly measured the frequency of unequal recombination in the hot-spot region using sperm from four normal individuals. Surprisingly, unequal recombination between the REPs occurs at a rate no greater than the average rate for the male genome (approximately 1 cM/Mb) and is the same as that expected for equally aligned REPs. This conclusion extends to humans the findings in yeast that recombination between repeated sequences far apart on the same chromosome may occur at similar frequencies to allelic recombination. Finally, the CMT1A hot-spot stands in sharp contrast to the human MS32 mini-satellite-associated hot-spot that exhibits highly enhanced recombination initiation in addition to positional specificity. One possibility is that the CMT1A hot-spot may consist of a region with genome average recombination potential embedded within a recombination cold-spot. (+info)
Analysis of a Charcot-Marie-Tooth disease mutation reveals an essential internal ribosome entry site element in the connexin-32 gene.
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A mutation located in the 5'-untranslated region (5'-UTR) of the nerve-specific connexin-32 mRNA, previously found in a family with Charcot-Marie-Tooth disease (CMTX), was analyzed for its effect on the expression of a reporter gene (luciferase) in transgenic mice and in transfected cells. Whereas both mutant and wild-type genes appeared to be transcribed and spliced efficiently, no luciferase was detected from the mutant in either system, suggesting that the mutation affects translation of the mRNA. When the 5'-UTR of nerve-specific connexin-32 mRNA was inserted between the two genes of a bicistronic vector and transfected into various cell lines, expression of the second gene was significantly increased. Because the mutant did not facilitate translation of the second gene in the bicistronic mRNA system, this result suggested that the CMTX mutation abolished function of an internal ribosome entry site (IRES) in the 5'-UTR of the wild-type connexin-32 mRNA. The CMTX phenotype of the mutant 5'-UTR further suggested that the wild-type IRES was essential for the translation of the connexin-32 mRNA in nerve cells. In addition, other sequence elements of the connexin-32 IRES were characterized by mutation analysis. A mutation in either of the first two elements investigated showed loss of IRES function, whereas mutation of a third element showed gain of function. (+info)