Some Genetic Variations May Be Particularly Difficult To Evaluate Using Current Stem Cell Modeling Techniques

New York, NY
 – March 13, 2017 /Press Release/  –– 

Some heritable but unstable genetic mutations that are passed from parent to affected offspring may not be easy to investigate using current human-induced pluripotent stem cell (hiPSC) modeling techniques, according to research conducted at The Icahn School of Medicine at Mount Sinai and published March 14, in the journal Stem Cell Reports. The study serves to caution stem cell biologists that certain rare mutations, like the ones described in the study, are difficult to recreate in laboratory-produced stem cells.

Stem cell-based disease modeling involves taking cells from patients, such as skin cells, and introducing genes that reprogram the cells into human-induced pluripotent stem cells (hiPSCs).  These “master cells” are unspecialized, meaning they can be pushed to become any type of mature cell needed for research, such as skin, liver or brain. The hiPSCs are capable of renewing themselves over a long period of time, and this emerging stem cell modeling technique is helping elucidate the genetic and cellular mechanisms of many different disorders.   

“Our study describes how a complex chromosomal rearrangement genetically passed by a patient with psychosis to her affected son was not well recreated in laboratory-produced stem cells,” says Kristen Brennand, PhD, Associate Professor of Genetics and Genomic Sciences, Neuroscience, and Psychiatry at the Icahn School of Medicine, and the study’s senior investigator. “As stem cell biologists dive into studying brain disorders, we all need to know that this type of rare mutation is very hard to model with induced stem cells.”

To investigate the genetic underpinnings of psychosis, the research team used hiPSCs from a mother diagnosed with bipolar disease with psychosis, and her son, diagnosed with schizoaffective disorder. In addition to the normal 46 chromosomes (23 pairs), the cells in mother and son had a very small extra chromosome, less than 1/10th normal size. This microduplication of genes is increasingly being linked to schizophrenia and bipolar disorders, and the extra chromosomal bit, known as a marker (mar) element, falls into the category of abnormally duplicated genes.

For the first time, the Mount Sinai research team tried to make stem cells from adult cells with this type of mar defect. Through the process, they discovered that the mar element was frequently lost during the reprogramming process.

While mar elements in the general population are rare (less than .05 percent in newborn infants), more than 30 percent of individuals with these defects are clinically abnormal, and mar elements are also significantly more likely to be found in patients with developmental delays.

The study found that the mother’s cells were mosaic, meaning some cells were normal while others were not, and the hiPSCs the team created accurately replicated that condition: some were normal and some had the extra mar chromosome. But the technique did not work well with the son’s cells. While all of his cells should have had the mar element, as with his mother, some of the reprogrammed stem cells did not contain the extra bit of chromosome.

“We realized we kept losing the mutation in the stem cells we made, and the inability to recreate cells with mar elements may hamper some neuropsychiatric research,” says Dr. Brennand. “The bottom line is that it is essential that stem cell biologists look for existing mar elements in the cells they study, in order to check that they are retained in the new stem cells.”

Researchers from Baylor College of Medicine, Cold Spring Harbor Laboratory, The University of California, San Diego, McLean Hospital, and Hoffmann-La Roche Ltd., contributed to this research.

The work was supported, in part, by NIH grants R01 MH101454, R21 MH097470, R21 MH1057321, RO1NS058529, R21 MH104505, New York Stem Cell Foundation, Brain and Behavior Young Investigator Grant, the Ellison Foundation, Anonymous Foundation, the Carmela and Menachem Abraham Fund and Team Daniel.

About the Mount Sinai Health System
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is in the “Honor Roll” of best hospitals in America, ranked No. 15 nationally in the 2016-2017 “Best Hospitals” issue of U.S. News & World Report.  The Mount Sinai Hospital is also ranked as one of the nation’s top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai’s Kravis Children’s Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals."

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