Charcot–Marie–Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit

Liu, Pentao; Wise, Carol A.; Chinault, A. Craig; Patel, Pragna I.; Lupski, James R.

doi:10.1038/ng1292-292

Cited by 352 publications

(226 citation statements)

References 42 publications

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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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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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“…In proximal 17p, for example, LCRs account for more than 23% of the genomic sequence, making this region a hotspot for NAHR [8]. Among the well-studied constitutional genomic disorders and rearrangements caused by LCRs in proximal 17p are the Charcot-Marie-Tooth disease type 1A duplication [9] and its reciprocal deletion, identified in patients with hereditary neuropathy with liability pressure palsies [10], and the SmithMagenis syndrome deletion and its reciprocal duplication, dup(17)(p11.2 p11.2) [11,12].…”

Section: Introductionmentioning

confidence: 99%

Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofibrosis

et al. 2005

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Non-allelic homologous recombination (NAHR) between low-copy repeats (LCRs) has been implicated recently in somatic rearrangements including isochromosome i(17q), which is associated with hematologic malignancies as well as solid tumors. In hematological malignancies, the most common i(17q) breakpoint results from LCR-mediated NAHR, which creates a dicentric chromosome, idic(17)(p11.2). We report an elderly patient who presented with primary myelofibrosis (MF) with myeloid metaplasia (MMM), associated with idic(17)(p11.2) as the sole chromosomal abnormality, making this the first idic(17)(p11.2) myeloproliferative case reported in which the breakpoints are mapped to the breakpoint cluster region in proximal 17p. The rearrangement breakpoint maps to the previously defined LCR cluster, further suggesting that the genomic architecture of proximal 17p may be responsible for the formation of the majority of i(17q) cases. We describe our development of a rapid screening test using interphase FISH to detect idic(17)(p11.2), discuss the potential prognostic value of this molecular diagnostic test, and examine the relevance of LCRmediated NAHR to common rearrangements in neoplasms. Am.

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“…A duplication on chromosome 17p12 was identified as the basis of Charcot-Marie-Tooth disease type 1 (CMT1A) (Lupski et al, 1991), whereas an interstitial deletion including the PMP22 gene was observed in patients with Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) (Chance et al, 1993). These distinct conditions represent prototypical disorders for the elucidation of the mechanism responsible for genomic disorders, as low copy repeats (LCRs) were identified in the region involved and nonallelic homologous recombination (NAHR) using these repeats as recombination substrates results in either the duplication or deletion (Pentao et al, 1992;Chance et al, 1994, Reiter et al, 1996Reiter et al, 1998).…”

Section: Charcot-marie-tooth Disease -Human Hereditary Neuropathy Witmentioning

confidence: 99%

Animal models for human contiguous gene syndromes and other genomic disorders

2004

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Genomic disorders refer to a group of syndromes caused by DNA rearrangements, such as deletions and duplications, which result in an alteration of normal gene dosage. The chromosomal rearrangements are usually relatively small and often difficult to detect cytogenetically. In a subset of such conditions the rearrangements comprise multiple unrelated contiguous genes that are physically linked and thus have been referred to as contiguous gene syndromes (CGS). In general, each syndrome presents a complex clinical phenotype that has been attributed generally to dosage sensitive gene(s) present in the responsible chromosomal interval. A common mechanism for CGS resulting from interstitial deletion/duplication has recently been elucidated. The DNA rearrangements result from nonallelic homologous recombination (NAHR) utilizing flanking low-copy repeats (LCRs) as recombination substrates. The resulting rearrangements often involve the same genomic region, a common deletion or duplication, making it difficult to assign a specific phenotype or endophenotype to a single responsible gene. The human and mouse genome sequencing projects, in conjunction with the ability to engineer mouse chromosome rearrangements, have enabled the production of mouse models for CGS and genomic disorders. In this review we present an overview of different techniques utilized to generate mouse models for selected genomic disorders. These models foment novel insights into the specific genes that convey the phenotype by dosage and/or position effects and provide opportunities to explore therapeutic options.

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Charcot–Marie–Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer unit

Cited by 352 publications

References 42 publications

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

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

Interphase FISH screening for the LCR-mediated common rearrangement of isochromosome 17q in primary myelofibrosis

Animal models for human contiguous gene syndromes and other genomic disorders

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