Identification of SMCHD1 domains for nuclear localization, homo-dimerization, and protein cleavage

Yosuke Hiramuki,Stephen J Tapscott

doi:10.1186/s13395-018-0172-z

Abstract

BackgroundSMCHD1 is a disease modifier and a causative gene for facioscapulohumeral muscular dystrophy (FSHD) type 1 and type 2, respectively. A large variety of different mutations in SMCHD1 have been identified as causing FSHD2. In many cases, it is unclear how these mutations disrupt the normal function of SMCHD1.MethodsWe made and analyzed lenti-viral vectors that express Flag-tagged full-length or different mutant SMCHD1 proteins to better understand the functional domains of SMCHD1 in muscle cells.ResultsWe identified regions necessary for nuclear localization, dimerization, and cleavage sites. Moreover, we confirmed that some mutants increased DUX4 expression in FSHD1 myoblasts.ConclusionsThese findings provide an additional basis for understanding the molecular consequences of SMCHD1 mutations.

Highlights

SMCHD1 is a disease modifier and a causative gene for facioscapulohumeral muscular dystrophy (FSHD) type 1 and type 2, respectively
A phenotypically identical form of FSHD2 is caused by mutations in SMCHD1, a member of the condensin/cohesin family of chromatin factors required for silencing some repetitive regions [4]
To identify the nuclear localization signal (NLS) in SMCHD1, we used immunofluorescence to determine the localization of Flag-tagged full-length and mutant SMCHD1 proteins in control myoblasts

Summary

Introduction

SMCHD1 is a disease modifier and a causative gene for facioscapulohumeral muscular dystrophy (FSHD) type 1 and type 2, respectively. A large variety of different mutations in SMCHD1 have been identified as causing FSHD2. In many cases, it is unclear how these mutations disrupt the normal function of SMCHD1. A phenotypically identical form of FSHD2 is caused by mutations in SMCHD1, a member of the condensin/cohesin family of chromatin factors required for silencing some repetitive regions [4]. FSHD2 requires the presence of a permissive haplotype of chromosome 4, which is characterized by specific single-nucleotide polymorphisms that create a polyadenylation signal for the DUX4 mRNA [3]. SMCHD1 is a disease modifier of FSHD1 [5]

Methods

Results

Discussion

Conclusion