DNA duplication associated with Charcot-Marie-Tooth disease type 1A

Lupski, James R.; Oca‐Luna, Roberto Montes de; Slaugenhaupt, Susan; Liu, Pentao; Guzzetta, Vito; Trask, Barbara J.; Saucedo‐Cárdenas, Odila; Barker, David F.; Killian, James M.; García, Carlos; Chakravarti, Aravinda; Patel, Pragna I.

doi:10.1016/0092-8674(91)90613-4

Cited by 1,218 publications

(717 citation statements)

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“…1 Hence, various microdeletion and duplication syndromes on chromosome 17 have been reported. [2][3][4][5][6][7] Deletions of chromosome band 17q24.2 are, however, rare. So far, only nine cases have been reported and five of these were large terminal aberrations ranging from 17q21.3 to qter.…”

Section: Introductionmentioning

confidence: 99%

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

et al. 2011

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Section: Introductionmentioning

confidence: 99%

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

et al. 2011

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“…Autosomaldominant CMT1 is the most frequent form (approximately 70% of CMT patients; Nelis et al 1996), and the genetic defect in the majority of cases is linked to chromosome 17p11.2-p12 (reviewed by Suter & Patel, 1994). This specific CMT1 subtype has been designated CMT1A and human molecular genetics has demonstrated a tight association with an intrachromosomal duplication of 1.5 Mb (Lupski et al 1991a;Raeymaekers et al 1991). Increased gene dosage was proposed as the underlying disease mechanism mainly based on the observation of abnormal nerve conduction velocity (NCV) in patients with segmental trisomies in this region ).…”

Section: Genetics Of Hmsnmentioning

confidence: 99%

Mouse genetics in cell biology

Mansuy¹,

Suter²

2000

Exp. Physiol.

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One of the most fascinating challenges in modern cell biology is the unravelling of the molecular mechanisms underlying the development and formation of functional organs, and the maintenance and regeneration of vertebrate tissues. In such processes, cell-cell interactions, mediated by direct contacts or secreted factors, and cell-extracellular matrix interactions are essential for the control of cell proliferation, migration, differentiation and death. These events are mediated by numerous molecular signals that have to be integrated within the cell to activate specific sets of regulatory factors responsible for correct spatial and temporal gene regulation. We are still far away from a complete understanding of these complex events at a molecular level but molecular genetic and genomic approaches have provided valuable tools and methodologies for the study of complex cellular functions in vivo. In particular, the development of reverse genetic methods such as transgene expression and gene targeting has allowed substantial progress in the understanding of the molecular mechanisms of cell-cell and cell-extracellular interactions. Although initially limited by a lack of spatial and temporal specificity, these approaches have recently undergone major developments partly overcoming these limitations, and have brought novel perspective into the application of genetic tools for the study of highly complex biological functions. To illustrate the power of genetic approaches in cell biology, we will describe in the first part of this review, several examples of mutant mice models that have allowed studies of developmental processes and neuron-glia interactions in the peripheral nervous system (PNS). The second part of the review will focus on recent advances of genetic approaches by describing the major methodologies, their latest developments and a few remarkable examples of their application in neurobiology and cancer research. Cell-cell and cell-extracellular matrix interactionsNeuronal and glial cell interactions in the nervous system Peripheral nerves are well suited to the study of the mechanisms of cell-cell interactions in organogenesis, a process in which cells determine the fate of their neighbours (Taylor & Suter, 1997;Jessen & Mirsky, 1999). This is exemplified in the process of myelination where two cell types, neurons and Schwann cells, exhibit a profound influence on each other. While axons regulate the proliferation and differentiation of Schwann cells, the latter are the main determinants of axon calibre and ion channel distribution. It has recently become clear that this cellular interdependence is not restricted to postnatal events, but that embryonic Schwann cell precursors and neurons also support each other for survival during critical periods of development. Furthermore, disturbance of the delicate balance between neuron and glia interactions by genetic manipulation has been revealed to be Genetic methodologies have provided powerful means for investigating the cellular and molecular mechanisms of ...

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“…Roughly half of these patients have CMT1A,2 a demyelinating neuropathy caused by a 1.4‐Mb duplication in chromosome 17p12 that contains the peripheral myelin protein 22 gene, PMP22 , an integral membrane protein expressed in PNS compact myelin 3, 4. CMT1A is hypothesized to occur as a result of nonallelic homologous recombination (NAHR)5, 6, 7 in a region of 17p12 surrounding and including the PMP22 gene, causing increased expression of the normal gene product.…”

Section: Introductionmentioning

confidence: 99%

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

Wang

Bai

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo determine whether predicted fork stalling and template switching (FoSTeS) during mitosis deletes exon 4 in peripheral myelin protein 22 KD (PMP22) and causes gain‐of‐function mutation associated with peripheral neuropathy in a family with Charcot–Marie–Tooth disease type 1E.MethodsTwo siblings previously reported to have genomic rearrangements predicted to involve exon 4 of PMP22 were evaluated clinically and by electrophysiology. Skin biopsies from the proband were studied by RT‐PCR to determine the effects of the exon 4 rearrangements on exon 4 mRNA expression in myelinating Schwann cells. Transient transfection studies with wild‐type and mutant PMP22 were performed in Cos7 and RT4 cells to determine the fate of the resultant mutant protein.ResultsBoth affected siblings had a sensorimotor dysmyelinating neuropathy with severely slow nerve conduction velocities (<10 m/sec). RT‐PCR studies of Schwann cell RNA from one of the siblings demonstrated a complete in‐frame deletion of PMP22 exon 4 (PMP22Δ4). Transfection studies demonstrated that PMP22Δ4 protein is retained within the endoplasmic reticulum and not transported to the plasma membrane.ConclusionsOur results confirm that that FoSTeS‐mediated genomic rearrangement produced a deletion of exon 4 of PMP22, resulting in expression of both PMP22 mRNA and protein lacking this sequence. In addition, we provide experimental evidence for endoplasmic reticulum retention of the mutant protein suggesting a gain‐of‐function mutational mechanism consistent with the observed CMT1E in this family. PMP22Δ4 is another example of a mutated myelin protein that is misfolded and contributes to the pathogenesis of the neuropathy.

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DNA duplication associated with Charcot-Marie-Tooth disease type 1A

Cited by 1,218 publications

References 37 publications

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

Mouse genetics in cell biology

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

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