Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2

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Abstract

Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by a contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here we show that mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

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Most cited references 44

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Protocol for the fast chromatin immunoprecipitation (ChIP) method.

Joel Nelson, Oleg Denisenko, Karol Bomsztyk (2006)

Chromatin and transcriptional processes are among the most intensively studied fields of biology today. The introduction of chromatin immunoprecipitations (ChIP) represents a major advancement in this area. This powerful method allows researchers to probe specific protein-DNA interactions in vivo and to estimate the density of proteins at specific sites genome-wide. We have introduced several improvements to the traditional ChIP assay, which simplify the procedure, greatly reducing the time and labor required to complete the assay. The simplicity of the method yields highly reproducible results. Our improvements facilitate the probing of multiple proteins in a single experiment, which allows for the simultaneous monitoring of many genomic events. This method is particularly useful in kinetic studies where multiple samples are processed at the same time. Starting with sheared chromatin, PCR-ready DNA can be isolated from 16-24 ChIP samples in 4-6 h using the fast method.

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A unifying genetic model for facioscapulohumeral muscular dystrophy.

Richard J. L. F. Lemmers, Patrick J. van der Vliet, Rinse Klooster … (2010)

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.

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DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy.

Linda N. Geng, Zizhen Yao, Lauren Snider … (2012)

Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 20 May 2013

Publication date (Electronic): 11 November 2012

Publication date (Print): December 2012

Publication date PMC-release: 04 June 2013

Volume: 44

Issue: 12

Pages: 1370-1374

Affiliations

[1 ]Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands

[2 ]Neuromuscular Disease Unit, Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA

[3 ]Department of Pediatrics, University of Washington, Seattle, Washington, USA. Seattle Children’s Hospital, Seattle, WA, USA

[4 ]Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands

[5 ]Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, Netherlands

[6 ]Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

[7 ]Department of Neurology, Academic Medical Center, Amsterdam, Netherlands

[8 ]Centre de référence des Maladies neuromusculaires and CNRS UMR6543, Nice University Hospital, Nice, France

[9 ]Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Author notes

[# ]Corresponding authors: Silvère M. van der Maarel, Ph.D. Leiden University Medical Center, Department of Human Genetics, Albinusdreef 2, 2333 ZA Leiden, The Netherlands, Phone: +31 71 526 9480, Fax: +31 71 526 8285, Maarel@ 123456lumc.nl . Stephen J. Tapscott, M.D., Ph.D. Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, Ph: 206-667-4499, FAX: 206-667-6524, stapscot@ 123456fhcrc.org . Daniel G. Miller, M.D., Ph.D. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Box 358056, 850 Republican Street, N416, Seattle, WA 98195-8056, Phone: 206 685 3882, Fax : 206 685 1357, dgmiller@ 123456uw.edu

[*]

These authors contributed equally to this study

[$]

Current address: Howard Hughes Medical Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

Article

Manuscript ID: NIHMS473788

DOI: 10.1038/ng.2454

PMC ID: 3671095

PubMed ID: 23143600

SO-VID: 5bdaa1a0-6861-4b15-84e9-2a1d34e29690

History

Funding

Funded by: National Center for Research Resources : NCRR

Award ID: UL1 RR024160 || RR

Funded by: National Human Genome Research Institute : NHGRI

Award ID: RC2 HG005608 || HG

Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS

Award ID: R01 AR045203 || AR