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| Rigid spine muscular dystrophy marker? The gene for human selenoprotein N (SEPN1), located on chromosome 1, is composed of 13 exons. It carries two codons (TGA) for the incorporation of selenocysteine when interacting with a secondary structural element called the selenocysteine insertion sequence (SECIS). (Adapted from Nature Genet. 2001, 29, 17-18) |
Muscular dystrophy (MD) is a congenital disorder characterized by progressive neuromuscular degeneration. A milder form, however, is rigid spine MD (RSMD), which is characterized by early rigidity of the spine and progressive nocturnal hypoventilation that requires ventilatory support.
Studying families with a history of RSMD, a research team headed by Pascale Guicheney at the Groupe Hospitalier Pitié-Salpêtrière (Paris) narrowed the location of the gene responsible for the disorder to a small portion of chromosome 1 containing ~100 genes. Recently, however, relying on several new microsatellite markers in the target region, the scientists narrowed the focus to a region containing about 20 genes and suggested a putative RSMD gene—that encoding selenoprotein N (SEPN1; Nature Genet. 2001, 29, 17-18).
Selenoproteins incorporate selenium through selenocysteine residues. These residues are encoded by the TGA codon, which is normally a stop codon but is co-opted for selenocysteine when present in an mRNA molecule that also contains a secondary structure element called a selenocysteine insertion sequence. The gene for SEPN1 has just such an element. Previous studies have shown a link between selenium and the pathophysiology of striated muscle. In livestock, there also is a correlation between selenium deficiency and MD.
In ten families studied, the researchers identified two frameshift, one nonsense, and three missense mutations, which either generate a truncated protein or make changes at highly conserved residues. Alternate mRNA splicing creates two forms of the selenoprotein, and although both are detected in skeletal muscle, brain, lung, and placenta, the shorter version predominates. Possible functions for selenoprotein N have yet to be identified, but its presence in skeletal muscle and the breathing difficulties of RSMD sufferers have prompted the researchers to speculate on a possible role for selenoprotein N in the physiology of muscles such as the diaphragm.
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