NICHD researchers identify cause of rare disease, Smith-Lemli-Opitz syndrome

Findings point to a potential strategy for treating the disorder

Smith-Lemli-Opitz syndrome (SLOS), a rare genetic disease that disrupts the nervous system and can lead to microcephaly and other brain defects, appears to result from a buildup of a cholesterol precursor called 7-dehydrocholesterol (7DHC), according to a new study by NICHD researchers. Their paper is published in the March 21, 2016, issue of Nature Medicine.


Cholesterol is an essential molecule. It serves as a structural component for cells and plays a role in several biological functions, including the development and activity of neurons in the brain. Cholesterol comes from food and is produced by the body, which is especially important for a growing fetus. Genetic disorders that impair the fetus’ ability to produce cholesterol may interfere with development to various degrees.

SLOS was first described in 1964. Its symptoms vary, ranging from fetal abnormalities to a spectrum of physical and neurological effects, often similar to autism, in children. SLOS currently has no cure or approved treatment. Researchers have studied experimental therapies that involve supplementing diets with cholesterol, but these approaches have limitations, partly because cholesterol does not cross easily into the brain.

The disease results from mutations in a gene called DHCR7, which helps carry out the last step of the body’s cholesterol production. The mutations lead to an accumulation of 7DHC and cholesterol deficiency, but researchers were unsure which of these problems is responsible for disease symptoms. Knowing the specific process that leads to a symptom allows researchers to identify potential therapeutic targets.


NICHD researchers developed a new model to study SLOS by inducing stem cells from skin samples of SLOS patients to form cells resembling neurons. The researchers found that abnormal neural development was caused by an accumulation of the cholesterol precursor 7DHC and not because of low cholesterol levels.

The team also discovered that excess 7DHC impaired Wnt/β-catenin, a key signaling process in the brain that regulates the development of neurons. In the SLOS model, 7DHC blocked Wnt activity, causing a loss of β-catenin protein.  Using an experimental drug called CHIR99021, the researchers were able to stabilize β-catenin protein, hinting at a potential strategy for treating the disease.


By showing how defective cholesterol production impairs neural development in SLOS, the study identifies potential targets for drug therapy, Wnt and β-catenin. Additionally, the researchers discovered that 7DHC accumulation, not cholesterol deficiency, is responsible for these effects.

According to the study authors, the findings are not limited to SLOS. Recent studies suggest a link between abnormal Wnt/β-catenin signaling and autism-like behaviors. “The interaction of cholesterol and Wnt proteins may have broader implications that could extend to other neurological disorders,” said lead author Forbes D. Porter, M.D., Clinical Director of NICHD’s intramural research program. “Modeling rare diseases with induced stem cells has provided valuable insight, and we’ll continue using this system to expand our findings.”


Francis KR, Ton AN, Xin Y, O’Halloran PE, Wassif CA, Malik N, Williams IM, Cluzeau CV, Trivedi NS, Pavan WJ, Cho W, Westphal H, and Porter FD. Modeling Smith-Lemli-Opitz syndrome with iPS cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes. Nature MedicineDOI: 10.1038/nm.4067 (2016)

Refer to caption.
Microscopy of healthy (left) and SLOS (right) stem cells developing into neurons. Neuron precursors form a "rosette" structure that is disrupted in SLOS cells.
Credit: NICHD
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