Richard J.L.F. Lemmers, Ph.D.,
Leiden, the Netherlands
Exciting news to report! A watershed paper was published online in Nature Genetics on November 11 that identifies the mutation in a gene causing the non-chromosome-4-linked FSHD disease called FSHD1B or FSHD2. FSHD has two types: FSHD1A and FSHD1B [aka FSHD2] that are clinically indistinguishable. FSHD1A is caused by the deletion of a repetitive stretch of DNA known as D4Z4 on the end of chromosome 4 and prior to this paper the cause of FSHD1B/FSHD2 cases was unknown. Now we know how they differ at the genetic level. A team of international researchers from the Netherlands, United States and France identified mutations in a gene on chromosome 18 at a second locus that cause FSHD2. The paper identifies mutations in the encoding Structural Maintenance of Chromosomes flexible Hinge Domain containing 1 (SMCHD1) gene, a chromatin modifier, SMCHD1 in the great majority of FSHD2 patients. With this finding, DNA diagnosis and counseling can now be offered. We also believe that this paper contributes to our understanding of the molecular pathophysiology of FSHD1A, identifies a novel target for therapy and represents the inaugural study on genetic modifiers of FSHD caused by truncation of D4Z4 on chromosome 4.
Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causesfacioscapulohumeral muscular dystrophy type 2
Richard J L F Lemmers , Rabi Tawil, Lisa M Petek, Judit Balog, Gregory J Block, Gijs W E Santen, Amanda M Amell, Patrick J van der Vliet, Rowida Almomani, Kirsten R Straasheijm, Yvonne D Krom, Rinse Klooster, Yu Sun, Johan T den Dunnen, Quinta Helmer, Colleen M Donlin-Smith, George W Padberg, Baziel G M van Engelen, Jessica C de Greef, Annemieke M Aartsma-Rus, Rune R Frants, Marianne de Visser, Claude Desnuelle, Sabrina Sacconi, Galina N Filippova, Bert Bakker, Michael J Bamshad, Stephen J Tapscott, Daniel G Miller & Silvère M van der Maarel
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 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 (encoding 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 D4Z4 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.
Paper by Nature Publishing Group found at Nature.com
Researchers saw that one parent had a mutation in their SMCHD1 gene and the other parent had the FSHD permissive chromosome 4 DUX4 variant, though D4Z4 is not shortened, from the other parent. Just as the loss of D4Z4 repeats below a threshold of 10 repeats on chromosome-4 causes expression of DUX4 in FSHD1A; the combination of chromosome-18 mutated SMCHD1 and permissive chromosome-4 haplotype 4QA161 with a normal length D4Z4 causes expression of DUX4 in FSHD1B/FSHD2.
The efforts of the FSH Society through its members and donors are acknowledged in the paper.
Congratulations are in order to FSH Society Scientific Advisory Board (SAB) members who are listed in the paper -- Drs. Rune Frants and George Padberg. We are especially pleased that the first and last authors, usually the principal contributors to the work, Drs. Silvere Van der Maarel and Richard Lemmers both of whom are FSH Society Marjorie Bronfman fellows and that middle author Yvonne Meijer-Krom who was able to work in Seattle as a FSH Society Marjorie Bronfman fellow are listed.
One measure of the FSH Society’s success has been the large number of FSHD researchers who have gained their start in FSHD research by virtue of a grant from the FSH Society. In many instances these young researchers have then gone on to receive much larger grants from the National Instututes of Health (NIH) and MDA USA, or other agencies while maintaining their allegiance and gratitude for the “seed money” received from us.
As you know the Society is constantly being asked to support more grant requests than we can finance—even when our SAB would otherwise recommend approval. It is our hope that you and others will be in a position to help us with this task of issuing grants to all worthy candidates, knowing that at some point we will find the cure which we are all diligently seeking.
It is an exciting time for the FSH Society and its remarkable achievements in the FSHD field.