PPM1D: A closer look at a rare genetic mutation using iPS Cell Research

One of the most extraordinary research advances in the past decade was the discovery of induced pluripotent stem (iPS) cells (also known as iPSCs). iPS cells are very special – they have the capacity to be turned into any cell type in the human body, including neurons. By generating iPS cells from children with autism spectrum disorders (ASD), intellectual and developmental disabilities (IDD), and certain psychiatric disorders, researchers can grow and study patient-specific neurons in the lab; a truly monumental achievement!

Dr. Herbert Lachman, a scientist at the Albert Einstein College of Medicine, is one of the first researchers to use iPS cells to study neurodevelopmental disorders. He is also one of the first to use a gene editing tool called CRISPR to introduce IDD and autism mutations into iPS cells as an alternative to generating patient-specific lines. He and his lab now want to apply iPS cell technology to study a certain class of PPM1D mutations, which are known to cause IDD. PPM1D mutations are an extremely rare cause of IDD. They were first identified by Dr. Sandra Jansen, et al. in 2017. Since this publication, the number of children identified with this mutation has nearly doubled and continues to grow as genetic testing becomes more readily available to families. In addition to IDD, PPM1D has been linked to ASD and a variety of other neurodevelopmental symptoms, such as gross and fine motor delays, anxiety and attention deficit disorder. Poor muscle tone and gastrointestinal difficulties also are known to occur.

In Dr. Lachman’s lab, his team plans to generate iPS cell lines from children with PPM1D mutations; additional lines will be made using CRISPR gene editing. These lines will be turned into neurons and cerebral organoids, which are small, 3-D structures that resemble the developing brain. The primary objective is to begin to uncover the underlying deficits in human neurons caused by PPM1D mutations using a variety of state-of-the art experimental techniques and link that to IDD. The Lachman lab is also interested in linking defects found in the PPM1D-mutated neurons with other genetic causes of ASD and IDD. Studies carried out over the past 10 years have resulted in the identification of hundreds of different genes that can cause IDD and ASD, and generally, no single gene accounts for more than ~0.5% of cases. By identifying functional connections across different genetic causes of IDD and ASD, our PPM1D studies could have an impact on children with different gene mutations, and vice versa. Thus, the impact of the research could extend well beyond the small PPM1D community. The ultimate goal, of course, is that the iPS cell research will lead to the development of novel treatments for children with IDD caused by PPM1D mutations and related genetic subtypes.

The Lachman lab has obtained funding from the National Institutes of Health (NIH) for several iPS cell initiatives. However, procuring NIH funding for ultra-rare genetic disorders, like PPM1D-associated IDD, is very difficult and can only be obtained with extensive preliminary data. Our plan is to raise money to generate iPS cell lines with PPM1D mutations and begin to identify deficits in neurons derived from these cells in order to generate preliminary data for a successful NIH application. Only through NIH funding can we begin to fully investigate how PPM1D mutations cause IDD. Please support this research by sending a tax-deductible donation by clicking on the donation link or sending a check payable to the PPM1D iPS cell research fund. Mail to:

Albert Einstein College of Medicine
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