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捆绑SM社区 microscopy expert spots identical defects in mice and severely ill children, leading to the discovery of a new syndrome

An extraordinary scientific coincidence has opened the door to potential treatments for newborn lung distress and chronic obstructive pulmonary disease (COPD).

A 捆绑SM社区 electron microscopy expert discovered identical defects in tissue samples taken from genetically engineered mice produced at New York University, and children suffering from a multi-organ disease being studied at Washington University School of Medicine in St. Louis.

The children were born with abnormally developed lungs, gastrointestinal and urinary systems, skin, skull, bones and muscles. All the children also had cutis laxa, an inherited connective tissue disorder that causes skin to hang loosely from the body. Three of the four patients died from respiratory failure before the age of 2. Details about the discovery were published Oct. 16 in the American Journal of Human Genetics.

Elaine C. Davis, Ph.D., senior author and an Associate Professor and Canada Research Chair in the Department of Anatomy and Cell Biology at 捆绑SM社区 in Montreal, Canada, compared various tissues from a mouse genetically engineered to be missing one form of the Ltbp4 gene with skin samples from one of the children using electron microscopy.

The mouse samples, provided by Daniel B. Rifkin, M.D., at New York University Langone School of Medicine, showed a remarkable similarity with respect to the appearance of the elastic fibers as the patient, who had cutis laxa together with lethal pulmonary complications and gastrointestinal and urinary disease.

"Elastic fibers are critical connective tissue structures that provide stretch and recoil to tissues such as vessels, lungs and skin," Davis explains. "When we age, our skin sags because of damage to the elastic fibers, however, some individuals are born with defective elastic fibers at birth, giving them a winkled and aged appearance as babies." Patients with cutis laxa clearly have defective elastic fibers, and one might believe that defects in the elastin gene would be the sole cause of the disease, however, "The assembly of elastic fibers is very complex, with more than 20 different proteins having been associated with the elastic fiber" Davis continues. "The cause of cutis laxa is therefore very difficult to determine with so many players."

Thus, it was pure coincidence that the Davis lab happened to be working on the two different projects for two different research teams at the same time that related to cutis laxa. The samples from the mouse model and patient were so strikingly similar, that when Davis first looked at the electron micrographs from the patient, she thought she was still looking at the mouse samples.

"I told my research assistant, Jiwon Choi, that I wanted to see the micrographs from the patient and not the mouse, which we had been studying for a few weeks," Davis said. Choi assured her that the electron micrographs were indeed from the patient. Davis immediately called Zsolt Urban at Washington University and said "I think I know what's wrong with these children."

Researchers in Urban's lab then sequenced the Ltbp4 gene in the children and confirmed that the patients had recessive mutations in the gene. "It was an exciting day when Zsolt called me to say that they had confirmed my prediction," Davis said.

The researchers determined that the patients were the first to show severe symptoms of a novel syndrome, which they have named Urban-Rifkin-Davis Syndrome (URDS). The findings have potential implications for newborns with underdeveloped lungs as well as older patients with severe lung diseases, including chronic obstructive pulmonary disorder, says first author Zsolt Urban, Ph.D., a Washington University School of Medicine pediatric geneticist.

"Many newborns commonly have breathing difficulties," Urban says. "Part of the problem is that the lung is not developed properly, especially the alveoli, the tiny sacs at the end of the smallest airways that serve as a place for oxygen uptake and gas exchange. This finding helped us identify a gene essential for the development of alveoli and potentially provide a target for intervention in premature babies."

Urban says potential treatments could include introducing the protein product of the gene to the newborn or using existing drugs that can moderate transforming growth factor beta (TGF脽), which is overactivated in the tissues of these children. The drug losartan, now in clinical trials for treating Marfan syndrome, another connective tissue disorder, has been shown to limit the effects of TGF脽 and merits further research as a possible future treatment.

The scientists now are broadening their research into the new syndrome among other patients with cutis laxa. Urban, an Assistant Professor of pediatrics, of medicine and of genetics at Washington University School of Medicine, heads the International Center for the Study of Cutis Laxa at St. Louis Children's Hospital. Urban and Davis have a long-standing collaboration to investigate the causes of cutis laxa.

"We are finding that about 70 percent of cutis laxa patients who have pulmonary, gastrointestinal and urinary problems have Urban-Rifkin-Davis Syndrome," Urban says. "Now, we will look at what percentage of cutis laxa patients who have only pulmonary problems have the mutation."

Early developmental problems that are not detectable in childhood may predispose a human to age-related disease, such as COPD, Urban says. Urban and colleagues are also testing samples collected from patients with COPD for LTBP4 mutations. When lungs are damaged with COPD, alveoli lose their elastic quality and the walls between them are destroyed as they become thick and inflamed.

"Patients who may have a slightly reduced activity of LTBP4 might be more susceptible for chronic lung diseases later in life," Urban says. "Identifying genes that are central for the formation of alveoli may help us devise ways to regenerate alveoli in patients with COPD."

"It's really rare for a discovery like this to come solely from the microscopy point of view," said Davis. "To pinpoint a genetic defect based simply on an electron microscopy image is just amazing. It will probably never happen again in my lifetime."