OGFRL1 and Cherubism

This summary addresses the association between OGFRL1 and cherubism, a rare craniofacial disorder marked by aggressive jawbone expansion. Cherubism is characterized by inflammatory fibrous lesions leading to progressive jaw destruction, a feature that significantly impacts affected children. Recent investigations have focused on cases that do not harbor the well‐established SH3BP2 mutations, thereby prompting an evaluation of alternative genetic contributors. In two independent families from Syria and India, homozygous loss‑of‑function variants in OGFRL1 were identified. These findings were discovered through whole exome sequencing and were notable for their absence in variant databases, emphasizing their potential pathogenicity. This association provides an important, albeit preliminary, insight that adds a new dimension to the genetic landscape of cherubism (PMID:38699440).

The genetic evidence stems from the identification of the homozygous variant c.337C>T (p.Arg113Ter) in two unrelated cherubism probands. Each family demonstrated an autosomal recessive pattern of inheritance with the affected individuals harboring the variant. Although the number of affected probands is limited and extended segregation data among additional relatives is not detailed, the recurrence in two independent families lends weight to the genetic association. The variant c.337C>T (p.Arg113Ter) satisfies the ClinGen criteria for a loss‑of‑function change and was consistently observed across the reported cases. This evidence suggests that OGFRL1 may play a contributory role in the pathogenesis of cherubism. However, the overall genetic evidence remains constrained by the small number of observations (PMID:38699440).

The inheritance mode in the investigated families is autosomal recessive, which is consistent with the biallelic loss‑of‑function nature of the identified variant. Careful evaluation of the segregation pattern within each family indicates that the homozygous state of the variant is found in the affected individuals. The reported variant, c.337C>T (p.Arg113Ter), was derived after removing extraneous transcript identifiers and adheres to HGVS nomenclature with three‑letter codes for amino acids. This variant is representative of the types of changes observed in loss‑of‑function mutations that typically lead to premature protein truncation. Despite the limited number of families, the occurrence of this variant in a recessive pattern provides a relevant piece of evidence for clinical decision‑making. Although additional segregation analysis would be beneficial, the current data support its inclusion in diagnostic panels for cherubism (PMID:38699440).

Extensive functional studies were conducted to evaluate the impact of OGFRL1 loss‑of‑function on cherubism pathology. Mouse models, including both OGFRL1 knockout mice and models carrying the Syrian frameshift mutation, were generated to recapitulate the human condition. Surprisingly, these animal models did not reproduce the characteristic jawbone destruction observed in human cherubism patients. Moreover, assays examining osteoclast formation and TNF‑α mRNA induction failed to demonstrate significant differences compared to wild‑type controls. This discrepancy highlights potential species‑specific differences in the functional consequences of OGFRL1 deficiency and raises questions about the direct pathogenic mechanism. Therefore, while the genetic evidence supports an association, the functional data are limited by the inability of the mouse models to mimic the human phenotype (PMID:38699440).

Integration of the genetic and experimental evidence reveals a nuanced picture. The identification of a clear loss‑of‑function variant in two independent cherubism families provides a basis for suspecting OGFRL1 as a novel candidate gene. However, the inability of animal models to replicate human disease features tempers the enthusiasm and suggests that additional factors may influence disease penetrance or expressivity in humans. This mixed evidence underscores the need for further research to resolve the observed discrepancies. The current findings, although limited, offer a promising avenue for expanding our understanding of cherubism genetics, especially in patients without SH3BP2 mutations. This association, therefore, presents a potential diagnostic marker while emphasizing the necessity for more comprehensive functional validation (PMID:38699440).

Key Take‑home sentence: OGFRL1 loss‑of‑function variants, while limited in number, represent a promising genetic marker for cherubism and should be considered in diagnostic settings, pending further functional validation to fully clarify their clinical utility. Continued evaluation and expanded studies are essential to confirm the clinical impact of these variants and to reconcile the differences observed between human pathology and animal model data. Clinicians and researchers should be aware of this tentative association as a potential contributor to cherubism etiology, particularly in cases lacking SH3BP2 mutations. The integration of genetic testing with thorough clinical assessment remains paramount. Future investigations are expected to further elucidate the role of OGFRL1 in jawbone homeostasis and its potential as a target for therapeutic intervention. Ultimately, this evidence serves as an important stepping‑stone towards improved diagnostic and therapeutic strategies for cherubism.

References

• JBMR plus • 2024 • Loss‑of‑function OGFRL1 variants identified in autosomal recessive cherubism families PMID:38699440

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