Significance
Goldenhar syndrome, sometimes referred to as oculo-auriculo-vertebral spectrum, is a rare condition that significantly affects how the face and skull develop. People with this syndrome often have abnormalities in the first and second pharyngeal arches, which can result in features like underdeveloped jaws, small or missing ears, and occasionally issues with their spine. Although this condition has been known about for many years, scientists still do not fully understand the genetic and molecular reasons behind it. A major difficulty in studying Goldenhar syndrome is how differently it can appear in different people. Some individuals might have only mild features, while others experience severe deformities. This wide range of symptoms makes it hard for researchers to pinpoint consistent genetic causes. Adding to the complexity, even within families, not everyone who inherits a genetic mutation shows the same symptoms. Scientists have identified a few genes, like MYT1 and FOXI3, that are linked to the condition, but these explain only a small percentage of cases. For most people with Goldenhar syndrome, the underlying genetic or molecular causes remain unknown. This leaves families with limited answers and makes it harder for doctors to offer clear diagnoses.
To address these challenges, new study published in Annals of the New York Academy of Sciences and conducted by Dr. Xiaomin Niu, medical student Fuyu Zhang, Wei Gu, Bo Zhang, and led by Professor Xiaowei Chen from the Chinese Academy of Medical Sciences & Peking Union Medical College investigated the role of a protein called Fibulin-2 (FBLN2). This protein, found in the extracellular matrix, is thought to play an important part in the development of cranial neural crest cells (CNCCs). These cells are essential for forming bones, cartilage, and connective tissue in the head and neck. If CNCCs do not properly migrate, grow, or mature, craniofacial anomalies can result, making them key to understanding conditions like Goldenhar syndrome. The researchers started by looking at a five-generation family tree with multiple members affected by the condition. They used whole-exome sequencing to search for rare genetic variants that might be linked to the syndrome. Through an advanced method called rare variant non-parametric linkage analysis, they zeroed in on FBLN2 as a possible culprit. The identified mutation, a missense variant, altered a key amino acid in the calcium-binding region of the Fibulin-2 protein. Using computational tools, they predicted that this change could seriously affect how the protein is shaped and how it functions, giving an important clue about its role in the syndrome. To confirm their findings, the team used zebrafish, which are a popular model for studying craniofacial development because their genetics and development are similar to humans in many ways. Using CRISPR/Cas9 gene-editing, they created a zebrafish line that lacked the fbln2 gene. When they examined the fish, they found noticeable craniofacial defects, such as malformed cartilage in the jaw and poorly organized chondrocytes. While normal zebrafish showed neat stacks of well-structured chondrocytes, the mutants had cells that were misshapen and misaligned. This clearly showed that FBLN2 plays a vital role in keeping craniofacial cartilage properly structured. The authors then wanted to understand better the molecular reasons behind these abnormalities. They analyzed markers involved in CNCC development and in the zebrafish missing fbln2, markers like sox9a and col2a1a, which are essential for chondrocyte differentiation, were significantly reduced. This demonstrated that without fbln2, CNCCs struggled to mature into functional chondrocytes and disrupted cartilage formation. They also explored whether fbln2 affected cell behavior, like growth and programmed cell death. By staining for dividing and dying cells, they found more apoptosis (cell death) and less proliferation (growth) in the CNCCs of mutant fish. These imbalances likely contributed to the severe craniofacial abnormalities observed, highlighting the importance of FBLN2 in CNCC survival and function. Finally, the team examined the BMP signaling pathway, a key regulator of CNCC development. In the mutants, they observed significantly lower activation of this pathway, particularly in the pharyngeal arches. This suggested that losing fbln2 disrupted BMP signaling, which is essential for guiding CNCCs in craniofacial development. Linking FBLN2 to this pathway revealed a critical mechanism behind the observed defects.
In conclusion, professor Xiaowei Chen and her team have made a significant advancement in our understanding Goldenhar syndrome and showed how the gene FBLN2 plays a key role in craniofacial development. Their research sheds light on the complex genetic and molecular mechanisms behind this rare condition, offering much-needed clarity for a disorder that has long puzzled scientists and clinicians. One of the most exciting implications of this work is how it could improve genetic testing. Now that FBLN2 has been highlighted as an important factor, clinicians might include it in genetic panels for craniofacial anomalies. This would allow earlier and more accurate diagnoses, particularly for families with a history of craniofacial disorders. It could also make genetic counseling and even prenatal diagnosis more precise, giving families clearer answers and better options moving forward. On the treatment front, the findings could lead to innovative therapies. Since the researchers linked FBLN2 mutations to problems in BMP signaling, they have pointed to a pathway that might be adjusted to help affected individuals. Targeting BMP signaling with drugs or biologics could potentially prevent or even correct some craniofacial defects. Additionally, the study underscores the importance of Fibulin-2 in the extracellular matrix, suggesting that therapies designed to restore this structural integrity might also prove beneficial. The impact of this research goes beyond Goldenhar syndrome. Fibulin-2’s role in CNCCs hints that it may be involved in other conditions linked to neural crest dysfunction, such as Treacher Collins syndrome. This discovery provides a framework for studying genetic and molecular pathways shared across multiple disorders, paving the way for broader applications.
Reference
Niu X, Zhang F, Gu W, Zhang B, Chen X. FBLN2 is associated with Goldenhar syndrome and is essential for cranial neural crest cell development. Ann N Y Acad Sci. 2024;1537(1):113-128. doi: 10.1111/nyas.15183.