The SALL4 gene provides instructions for making a protein that acts as a transcription factor. This means the SALL4 protein functions like a master switch, attaching to specific regions of DNA and controlling the activity of many other genes. While it is a powerful regulator, its role is temporary and focused on the earliest stages of life. The SALL4 protein is particularly important during embryonic development, where it helps orchestrate the formation of various body structures. It exists in different forms, with isoforms A and B being the most extensively studied for their distinct functions.
The Role of SALL4 in Early Development
The SALL4 gene is highly active during the initial phases of embryonic and fetal development, beginning as early as the two-cell stage of an embryo. The protein it produces is a significant factor in maintaining the pluripotency of embryonic stem cells, which are cells capable of developing into any cell type in the body. SALL4 works within a complex network, interacting with other key pluripotency factors such as Oct4 and Nanog, to ensure stem cells retain their undifferentiated state and self-renewal capacity. If SALL4 levels are reduced or absent, these pluripotent cells can lose their “stemness” and begin to differentiate prematurely, disrupting normal developmental processes.
Beyond maintaining stem cell identity, SALL4 also guides the formation of specific organs and body parts. It plays a role in the proper development of the limbs, including the arms and hands. The protein is also involved in the development of nerves that control eye movement and the formation of the internal walls that divide the heart into its separate chambers.
SALL4 Gene Mutations and Associated Syndromes
When there is a mutation in the SALL4 gene, it can lead to various congenital conditions. The most recognized of these is Okihiro syndrome, also known as Duane-radial ray syndrome. This condition is passed down in an autosomal dominant pattern, meaning only one copy of the mutated SALL4 gene is sufficient for the syndrome to manifest.
Individuals with Okihiro syndrome often present with characteristic abnormalities of the upper limbs, which can range from mild issues like missing or underdeveloped thumbs to more significant defects involving the radius bone in the forearm. Another defining feature is Duane anomaly, an eye movement disorder where the affected eye has difficulty moving outward, often retracting into the socket and causing the eyelid opening to narrow when attempting to look inward. The severity of these symptoms can vary widely even among family members carrying the same SALL4 mutation.
Beyond the limbs and eyes, Okihiro syndrome can involve other body systems. Affected individuals may experience hearing loss, and some can have kidney abnormalities, ranging from structural differences to impaired function. Heart malformations, and issues with the external ears or anal region have also been reported. Most SALL4 gene mutations associated with these syndromes lead to a premature stop signal in the genetic instructions, resulting in a shortened or non-functional protein, a mechanism known as haploinsufficiency.
Reactivation of SALL4 in Cancer
In healthy adults, the SALL4 gene is turned off in most differentiated tissues, having completed its role in early development. However, in certain types of cancer, this gene can become reactivated, which contributes to the uncontrolled growth and spread of malignant cells. When SALL4 is reactivated, it can act as an oncogene, promoting the characteristics of cancer cells.
The re-expression of SALL4 in adult cells can confer stem-like properties to cancer cells, including the ability to self-renew, increase mobility, invade surrounding tissues, and develop resistance to chemotherapy. This reactivation is particularly noted in specific cancer types. SALL4 is found in germ cell tumors, especially yolk sac tumors, where it serves as an important diagnostic marker.
It is also reactivated in hepatocellular carcinoma, a form of liver cancer, and in various leukemias, including acute myeloid leukemia (AML) and mixed lineage leukemia-rearranged leukemia. SALL4’s role in cancer involves its ability to repress the expression of tumor suppressor genes. Furthermore, it can activate signaling pathways like Wnt/β-catenin, PI3K/AKT, and Notch.
Medical and Diagnostic Significance
The distinct functions of SALL4 in both normal development and disease have given it medical and diagnostic significance. In cases of suspected inherited developmental disorders, genetic testing for mutations in the SALL4 gene can provide a definitive diagnosis for conditions like Okihiro syndrome. This helps clinicians understand the underlying cause of a patient’s symptoms and can guide management.
Beyond inherited syndromes, the presence of the SALL4 protein serves as a valuable biomarker in oncology. Its detection assists in diagnosing specific cancers. The level of SALL4 expression can also offer insights into a tumor’s aggressiveness and predict patient outcomes, with higher levels often correlating with a poorer prognosis and increased risk of recurrence. Because SALL4 is absent in most healthy adult tissues but re-expressed in many cancer types, it is being explored as a target for the development of cancer therapies.