A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

Peter Meinke; Alastair Kerr; Rafal Czapiewski; Jose de las Heras; Manfred Wehnert; Eric Schirmer; Elizabeth Harris; Heike Kölbel; Francesco Muntoni

doi:10.1016/j.ebiom.2019.11.048

A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

Peter Meinke, Alastair Kerr, Rafal Czapiewski, Jose de las Heras, Manfred Wehnert, Eric Schirmer, Elizabeth Harris, Heike Kölbel, Francesco Muntoni

School of Biological Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Limitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.

Original language	English
Article number	102587
Journal	EBioMedicine
Volume	51
Early online date	17 Dec 2019
DOIs	https://doi.org/10.1016/j.ebiom.2019.11.048
Publication status	Published - 1 Jan 2020

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10.1016/j.ebiom.2019.11.048Licence: Creative Commons: Attribution (CC-BY)

1-s2.0-S2352396419307972-mainFinal published version, 8.35 MBLicence: CC BY

Nuclear Envelope Directed Genome Organisation in Myogenesis and Emery-Dreifuss Muscular Dystrophy
Schirmer, E. (Principal Investigator)
MRC
1/08/18 → 31/07/22
Project: Research
Nuclear envelope transmembrane protein regulation of tissue-specific genome organisation and cell cycle regulation
Schirmer, E. (Principal Investigator)
UK-based charities
1/08/11 → 31/07/19
Project: Research

Eric Schirmer
- School of Biological Sciences - Personal Chair of Nuclear Envelope Biology
Person: Academic: Research Active

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Meinke, P., Kerr, A., Czapiewski, R., de las Heras, J., Wehnert, M., Schirmer, E., Harris, E., Kölbel, H., & Muntoni, F. (2020). A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism. EBioMedicine, 51, Article 102587. https://doi.org/10.1016/j.ebiom.2019.11.048

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title = "A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism",

abstract = "Limitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.",

author = "Peter Meinke and Alastair Kerr and Rafal Czapiewski and {de las Heras}, Jose and Manfred Wehnert and Eric Schirmer and Elizabeth Harris and Heike K{\"o}lbel and Francesco Muntoni",

year = "2020",

month = jan,

day = "1",

doi = "10.1016/j.ebiom.2019.11.048",

language = "English",

volume = "51",

journal = "EBioMedicine",

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Meinke, P, Kerr, A, Czapiewski, R , de las Heras, J, Wehnert, M, Schirmer, E, Harris, E, Kölbel, H & Muntoni, F 2020, 'A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism', EBioMedicine, vol. 51, 102587. https://doi.org/10.1016/j.ebiom.2019.11.048

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T1 - A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

AU - Meinke, Peter

AU - Kerr, Alastair

AU - Czapiewski, Rafal

AU - de las Heras, Jose

AU - Wehnert, Manfred

AU - Schirmer, Eric

AU - Harris, Elizabeth

AU - Kölbel, Heike

AU - Muntoni, Francesco

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Limitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.

AB - Limitations of genome-wide approaches for genetically-heterogenous orphan diseases led us to develop a new approach to identify novel Emery-Dreifuss muscular dystrophy (EDMD) candidate genes. We generated a primer library to genes: (I) linked to EDMD, (II) mutated in related muscular dystrophies, (III) highlighted from limited exome sequencing, (IV) encoding muscle-specific nuclear membrane proteins. Sequencing 56 unlinked EDMD patients yielded confirmed or strong candidate alleles from all categories, accounting for most remaining unlinked patients. Known functions of newly-linked genes argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction through connectivity of candidates from the nuclear envelope to the plasma membrane.

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DO - 10.1016/j.ebiom.2019.11.048

M3 - Article

SN - 2352-3964

VL - 51

JO - EBioMedicine

JF - EBioMedicine

M1 - 102587

ER -

A multistage sequencing strategy pinpoints many novel and candidate disease alleles for orphan Disease Emery-Dreifuss Muscular Dystrophy and Supports Gene Misregulation as its Pathomechanism

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Nuclear Envelope Directed Genome Organisation in Myogenesis and Emery-Dreifuss Muscular Dystrophy

Nuclear envelope transmembrane protein regulation of tissue-specific genome organisation and cell cycle regulation

Profiles

Eric Schirmer

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