Novel and recurrent EMD mutations in patients with Emery–Dreifuss muscular dystrophy, identify exon 2 as a mutation hot spot

Brown, Charlotte A.; Scharner, Juergen; Felice, Kevin J.; Meriggioli, Matthew N.; Tarnopolsky, Mark A.; Bower, Matthew; Zammit, Peter S.; Mendell, Jerry R.; Ellis, Juliet A.

doi:10.1038/jhg.2011.65

Cited by 30 publications

(18 citation statements)

References 38 publications

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“…It is possible that Patient 1's MRI brain findings are related to involvement of this gene, as Patient 3's MRI was reported as normal (Patient 2's parents did not consent to MRI). GDI1 has been linked to X-linked intellectual disability, [16] while mutations in the Emerin (EMD) gene lead to X-linked Emery-Dreifuss muscular dystrophy [17]. As gain-of-function mutations of EMD are yet to be reported, it is difficult to predict the influence that this gene duplication will have on our patient.…”

Section: Discussionmentioning

confidence: 76%

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

Chow¹,

Lai²,

Brett³

et al. 2015

J Clin Med Genomics

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The methyl-CpG-binding protein 2 gene (MECP2) on the X chromosome encodes an essential epigenetic regulator in human postnatal brain development. Increased dosage of MECP2 causes a severe syndromic form of intellectual disability, the MECP2 duplication syndrome. Males with this syndrome have a progressive neurological disorder, severe to profound intellectual disability, epilepsy and recurrent respiratory infections. We report three cases with copy number gain in Xq28 involving the MECP2 gene. The gains were detected by chromosomal microarray analysis and ranged in size from 300 kb to 4.96 Mb. The three boys were aged between 3 and 16 years old. All three had development delay and no speech. In addition, one patient was diagnosed with Lennox-Gastaut syndrome and another had a Dandy Walker variant. Their clinical features were compared with other reported cases. We concluded that all three patients' clinical features were due to the Xq28 duplication, which confirmed the utility of chromosomal microarray analysis as a first-tier test in patients with unexplained intellectual disability. With a specific genetic diagnosis, we were able to provide appropriate anticipatory guidance for these patients and their families.

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Section: Discussionmentioning

confidence: 76%

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

Chow¹,

Lai²,

Brett³

et al. 2015

J Clin Med Genomics

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“…While pathogenic variants have been identified throughout the EMD gene, exon 2 has been reported as a mutational hotspot (Brown et al. 2011). This c.187+1G>T splice variant is also at the exact position of a previously reported c.187+1G>A pathogenic variant in EDMD (Deymeer et al.…”

Section: Discussionmentioning

confidence: 99%

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

Hunter

Ahearn

Balak

et al. 2015

Molec Gen & Gen Med

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Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.

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“…Proteins with larger exposed domains (> 60 kD) fail to accumulate at the inner membrane 70 . Alternative mechanisms to reach the inner membrane 71 , 72 may not apply to emerin; emerin lacks “FG-repeats” and its predicted nuclear localization signal (residues 35–47) 73 , 74 is not required for nuclear import, 75 as discussed below (Fig. 3).…”

Section: Emerin Biogenesis and Nuclear Envelope Localizationmentioning

confidence: 99%

The nuclear envelope LEM-domain protein emerin

Berk

Tifft

Wilson

2013

Nucleus

138

181

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Emerin, a conserved LEM-domain protein, is among the few nuclear membrane proteins for which extensive basic knowledge—biochemistry, partners, functions, localizations, posttranslational regulation, roles in development and links to human disease—is available. This review summarizes emerin and its emerging roles in nuclear “lamina” structure, chromatin tethering, gene regulation, mitosis, nuclear assembly, development, signaling and mechano-transduction. We also highlight many open questions, exploration of which will be critical to understand how this intriguing nuclear membrane protein and its “family” influence the genome.

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Novel and recurrent EMD mutations in patients with Emery–Dreifuss muscular dystrophy, identify exon 2 as a mutation hot spot

Cited by 30 publications

References 38 publications

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

Cytogenomic Delineation and Clinical Characterization of Three Cases of MECP2 Duplication Syndrome

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

The nuclear envelope LEM-domain protein emerin

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