An MDA-supported group including Winokur, Wasmuth ( posthumously) and Altherr publishes a paper suggesting that FSHD could arise through one of three mechanisms: altered chromatin structure; improper location of the FSHD region of chromosome 4 in the cell nucleus; or deletion of a part of a gene lying inside the FSHD region. 1996
French physicians Louis Landouzy and Joseph Dejerine describe a family with a distinct form of muscular dystrophy that preferentially affects facial, upper arm and shoulder muscles.
Research teams from the United States, United Kingdom and the Netherlands, supported in part by MDA, refine the location of the mutation to a small region near one end of chromosome 4. 1991-93
Disease is further defined through studying patients in the Netherlands.
Dutch scientists map the location of the FSHD genetic mutation to chromosome 4. 1990
MDA grantees Tupler and Davide Gabellini, with colleagues
in the United States and Italy, breed mice that overexpress the
FRG1 gene, which lies near the D4Z4 region. The mice have
high levels of the FRG1 protein and develop an FSHD-like
MD. The researchers suggest that FRG1 is involved in how
cells follow genetic instructions for protein synthesis. MDA-
funded van
der Maarel
and col-
leagues
provide
additional
evidence that
FRG1 plays
a role in the
processing
of genetic
instructions.
Tupler and colleagues propose that FSHD results from the failure of a molecular brake to stick to the disease-associated region of chromosome 4 (D4Z4) and thereby suppress gene expression; they say that missing DNA in this region keeps the brake away from its normal position.
Clinical features of what’s now called facioscapulohumeral MD are further defined in a large Utah family with the disease.
Course of disease is understood as variable, with spread from upper body weakness to weakness of lower leg, hip or abdominal muscles often seen. Mild hearing loss and retinal abnormalities are noted as part of FSHD; involvement of cardiac or respiratory muscles occurs, but rarely.
MDA grantee Rossella Tupler and colleagues find that many genes are incorrectly regulated in FSHD-affected muscle tissue; they suggest that a mutation in one gene may cause the global misregulation.
An MDA-supported team that 1994 includes Sara Winokur, John Wasmuth and Michael Altherr suggests that a position effect involving shifting of a gene toward a region of closed chromatin may underlie FSHD.
2003 A group that includes MDA grantee Silvere van der Maarel proposes that an abnormally short D4Z4 region may cause unusual looping of chromosome 4, resulting in aberrant interactions of D4Z4 with distant genes. MDA-funded Winokur and colleagues propose that FSHD is caused by an abnormal positioning of the tip of chromosome 4 in the cell nucleus, with widespread consequences for gene regulation.
Emery-Dreifuss MD and one form of limb-girdle MD. “How do they come about? We don’t really know the answer to that, but one hypothesis is that those nuclear envelope proteins somehow regulate gene expression.
“We’re suggesting that, since this chromatin region clearly localizes to
[is located at] the nuclear envelope, it’s she says, “but it could be that, because
certainly possible that there are altera- this region is now in a particular com-
tions in how that chromatin can interact partment in the nucleus, and there are
withthe nuclear envelope. The chroma- other regions of the genome that also
tin itself has changed, and therefore the localize to this compartment, there may
interactions with the nuclear envelope be interactions between the FSHD region
might be different. and those other regions. So that’s how it
“Local genes may well be affected,” may be that there’s a broader effect.”
References:
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