Dystrophin mutations: plus to minus

Margarita Paimakova, Vesti 

One in 3,500 boys born in the world inherits mutations that cause the body to produce the wrong version of the protein dystrophin. As a result, such a child develops currently untreatable Duchenne muscular dystrophy (Duchenne muscular dystrophy).

The disease manifests itself in boys, since the dystrophin gene is located on the X chromosome. That is, in order for the disease to develop in a girl, she must inherit two copies of the mutant gene.

The protein dystrophin helps muscle fibers stick together, and its absence disrupts the regenerative cycle that rebuilds muscle tissue. Eventually, the muscles in the body of a sick person are replaced by fatty and connective tissue, and people with Duchenne muscular dystrophy often find themselves confined to a wheelchair even in adolescence. Most of them eventually do not live to be 30 years old.

As you know, many diseases and methods of their treatment are modeled on animals. In the case of muscular dystrophy, dogs are used. Some female golden retrievers are carriers of the dystrophin mutation, which causes the disease in male puppies. Dog breeders, as a rule, can exclude such risks with the help of a genetic examination of individuals. However, Mayana Zatz, a geneticist from the University of Sao Paulo, together with her colleagues specially breeds puppies with mutations. It is clear that such dogs are doomed to death in the name of science.

Not so long ago, researchers from Brazil studied and described Ringo, a golden retriever born in a kennel in 2003. Unlike many of his brothers, he survived: Ringo's muscles, like other puppies from the same litter, did not degrade.

DNA testing showed that Ringo and his brothers, despite the miraculous rescue, still inherited dystrophin mutations. Puzzled researchers decided to closely observe unusual dogs in a specially equipped laboratory for this purpose – one in which sick animals are more or less comfortable to live, scientists emphasize.

Ringo has fathered a total of 49 puppies from 4 different females. One of these puppies, named Suflair, also did not demonstrate the appearance of muscular dystrophy, despite inheriting a faulty gene.

Scientists compared the genomes of Ringo and Prompter with the genome of other golden retrievers suffering from muscular dystrophy, and revealed a mutation in the gene encoding the Jagged1 protein that is not characteristic of other dogs in the colony (a total of 31 individuals).

The muscles of Ringo and his son showed higher levels of the Jagged1 protein compared to the muscles of sick dogs. When the researchers introduced this mutation into the embryos of danio-rerio fish, which also lacked dystrophin, this kind of manipulation protected the fish from muscle tears and other symptoms of muscular dystrophy.

Scientists still can't say for sure exactly how higher levels of the Jagged1 protein protect dogs from muscular dystrophy. This protein is involved in a variety of biological processes, including muscle development and regeneration.

Perhaps this mutation somehow compensates for the regeneration problems caused by the absence of dystrophin.

Currently, Brazilian scientists are trying to find drugs that will promote the production of higher levels of Jagged1 in mice and danio-rerio fish (both are also model organisms, while it is easier to grow them and observe their relatively short lives).

Experts believe that a mutation that opposes muscular dystrophy may indicate new methods of treating not only Duchenne muscular dystrophy, but also other causes of muscular atrophy, including age.

Ringo died last year at the age of 11, which corresponds to the normal life span of golden retrievers. The prompter is currently 10 years old – he still walks, although he can no longer jump.

A scientific article about unusual dogs was published by Cell: Vieira et al., Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

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16.11.2015