New insights into the genetic basis of facioscapulohumeral muscular dystrophy, one of the more common forms of muscular dystrophy, suggest that the disorder may arise only in people with specific chromosomal variants that permit the unusual stability of a pathogenic gene transcript.
Prior to the current discovery by Richard J.L.F. Lemmers, Ph.D., of Leiden (Netherlands) University Medical Center and his colleagues (Science 2010;329:1650-3), the complexity of the genetic setting in which facioscapulohumeral muscular dystrophy (FSHD) skvelops has long hampered efforts to unravel the pathogenic mechanism of the disease.
Most people have a long repeated sequence of nucleotide bases called a macrosatellite repeat array on chromosome 4q35. In healthy people, this 3.3-kilobase sequence on 4q35, called D4Z4 repeats 11-100 times. Patients with autosomal dominant FSHD have a shortened array, with only 1-10 D4Z4 units. At least one D4Z4 unit is necessary to cause FSHD. A nearly identical repeat array also occurs on chromosome 10q, but a decrease in the number of repeated units on that chromosome has not been known to cause FSHD.
Other studies have shown that translocated copies of the repeated units from either chromosome 4 or 10 are often found on the end of either chromosome. But FSHD is known to occur with only certain variants of the repeat array that is found on the end of chromosome 4q.
The major transcript from each D4Z4 unit is the DUX4 gene, which codes for a double homeobox protein. But none of these transcripts has appeared to be stable except for a transcript of DUX4 from the distal D4Z4 unit. After observing that only one D4Z4 unit is necessary to cause FSHD, Dr. Lemmers and his associates chose to examine what makes the transcriptional profile of the distal unit pathogenic.
They found that a nucleotide sequence termed pLAM that lies next to the distal D4Z4 unit gives stability to the unit's DUX4 transcript. This sequence was not found in other D4Z4 repeat-array configurations of other variants of chromosome 4q or chromosome 10q.
This finding suggested to the researchers that “FSHD may arise through a toxic gain of function attributable to the stabilized distal DUX4 transcript.”
Dr. Lemmers and his colleagues then studied four families with one or more affected individuals who carried unusual hybrid D4Z4 repeat-array structures composed of units from chromosome 4q and 10q. This repeat array in one affected individual even resided on chromosome 10 rather than chromosome 4, which indicated that genes nearby the repeat array on chromosome 4q do not play a key role in the pathogenesis of FSHD. This means that when the last D4Z4 unit and its nearby pLAM sequence are found together, they cause the disease regardless of their chromosomal location.
The study “not only explains the striking chromosome specificity of the disorder, but also provides a genetic mechanism that may unify the genetic observations in patients with FSHD,” the researchers concluded.
The study was supported by grants from 11 organizations, health and science agencies, and foundations.
Report by Jeff Evans, Managing Editor.
Adviser's Viewpoint
'Toxic Gain of Function' Not Unique
Richard J.L.F. Lemmers, Ph.D., and colleagues, part of an international consortium of scientists probing the causes of facioscapulohumeral muscular dystrophy (FSHD), have come upon a coherent genetic model of this disease that ties up many of the confusing loose ends of the FSHD puzzle, a subject which has long baffled researchers in the field and clinicians who care for FSHD patients and their families. In their report, Dr. Lemmer and coworkers found that all FSHD patients the group studied had an identical DNA sequence in the last D4Z4 unit and the immediate flanking pLAM sequence of genetic material. Quite remarkably, the specific gene sequence variants appear to convey pathogenicity to the repeat whether they occur on chromosome 4 (the traditional site of the FSHD gene) or chromosome 10. Furthermore, they propose that this faulty terminal D4Z4 unit and adjacent pLAM sequence mediate what has been termed a “toxic gain of function.”
Other neurologic disorders are known to be caused by a toxic gain of function, most notably familial amyotrophic lateral sclerosis, where a superoxide dismutase 1 (SOD1) mutation is responsible for the condition, and Huntington's disease, where CAG repeats are thought to mediate the disease. Toxic gain of function has been proposed as a mechanism in other diseases as well, including idiopathic Parkinson's disease, where alpha synuclein aggregates lead to degeneration of mesencephalic neurons, and Alzheimer's disease, where tau phosphorylation in the hippocampus is thought to lead to neuronal deterioration.